Send Orders of Reprints at bspsaif@emirates.ae
Anti-Cancer Agents in Medicinal Chemistry, 2013, 13, 000-000

1

Type II Ki...
2 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0
Table 1.

Blanc et al.

Comparison Between the Different...
Type II Kinase Inhibitors

Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0

N
N

N

N

H
N

HN
HO

N

N

N...
4 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0

A)

Blanc et al.

B)

PD318088
Val127

I

Ser212
F

F
H...
Type II Kinase Inhibitors

Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0

5

O

O
N

O

N

N
H

O
N

CN
...
6 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0

A)

Blanc et al.

B)

Imatinib (STI-571)
Ile360
His361
...
Type II Kinase Inhibitors

Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0
CF3

N

N

H
N

N

H
N

O

O

O...
8 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0
Table 2.

Blanc et al.

Molecules that are Either FDA Ap...
Type II Kinase Inhibitors
Table 3.
Generic
Name

Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0

Molecule...
10 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0

Blanc et al.

First Generation Bcr-Abl inhibitors
N

N...
Type II Kinase Inhibitors

For suppressing mutant resistance, researchers have recently
come up with several strategies in...
12 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0

3.4.3. Design Drugs for the “Switch Control Pocket” Th...
Type II Kinase Inhibitors

5. CONFLICT OF INTEREST
The authors declare that there is no conflict of interest in this
revie...
14 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0
[18]

[19]

[20]

[21]

[22]

[23]

[24]
[25]
[26]

[27...
Type II Kinase Inhibitors
[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]
[60]

[61]
[62]

Taguchi, E.; N...
16 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0
[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[...
Type II Kinase Inhibitors

[102]

Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0

Jinnai, I.; Matsuo, K.;...
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Review anti-cancer agents in medicinal chemistry, 2013

  1. 1. Send Orders of Reprints at bspsaif@emirates.ae Anti-Cancer Agents in Medicinal Chemistry, 2013, 13, 000-000 1 Type II Kinase Inhibitors: An Opportunity in Cancer for Rational Design Javier Blanc1,*, Raphaël Geney2 and Christel Menet1 1 Department of Medicinal Chemistry, Galápagos NV, Mechelen, Belgium; 2Department of Computational and Structural Sciences, Galápagos SASU, Romainville, France Abstract: With the advent of the Type II kinase inhibitor imatinib (Gleevec) for treatment against cancer, rational design of tailored molecules has brought a revolution in medicinal chemistry for treating tumours caused by kinase malfunctioning. Among different types of kinase inhibitors, the design of Type II inhibitors has been rationalized for maximizing the benefits and reducing drawbacks. Here we highlight the development made in Type II inhibitors, discussing the advantages and disadvantages of these types of molecules. Furthermore, we present the strategies for designing druggable molecules that either selectively inhibit target kinases or overcome drug resistance. Keywords: Allosteric inhibitors, cancer, covalent inhibitors, DFG-in, DFG-out, kinase inhibitors, Type I inhibitors, Type II inhibitors, Type III inhibitors, Type IV inhibitors. 1. INTRODUCTION Cancer can be characterized as a disorder in which affected cells suffer from abnormal growth due to the malfunctioning of inherited or acquired DNA. This malfunctioning causes invasion, compromise and destruction of tissues and promotion of neovascularisation for survival of the cancer. Often metastasis is formed, that spreads the tumoural cells throughout the body via the lymphatic system and the bloodstream. Cancer accounts for more than 100 distinct diseases presenting diverse risk factors and epidemiology and is therefore held be responsible for one in eight deaths worldwide [1]. At present, there are a number of therapies available for the treatment of cancer such as chemotherapy, radiotherapy, hormonal therapy, monoclonal antibody therapy and surgery. These treatments are suggested on the basis of the type and nature of the tumour; location and stage of the cancer; performance of the therapy and drug resistance; as well as the general health of the patient. Various such treatments have been introduced against key biological functions in cancer such as signal transduction cascades [2]. Recent years have observed the emergence of the kinase family (Ser/Thr and Tyr kinase) as one of the most intensively pursued target classes because of its intimate involvement in oncogenic signal transduction pathways that present multiple physiological responses, tumour cell proliferation and cell survival [3]. On the basis of this research, the FDA has approved several smallmolecule tyrosine-kinase inhibitors for treating cancer [4, 5]. The classification of these molecules depends on the region of interaction in the kinase and reversibility of the inhibition as Type I, Type II, Type III, Type IV and covalent inhibitors (Table 1). Among several types of Ser/Thr [6] and Tyr kinase inhibitors, this review is focused primarily on Tyr kinase inhibitors. The review starts with the introduction of different types of tyrosine kinase inhibitors which have been summarized by Ser/Thr kinase inhibitor classification analogy of Cozza’s review [6]: Type I, Type II, Type III, Type IV and covalent inhibitors (literature reports on Type V inhibitors for Tyr kinases have not been presented by the authors in this review). Finally, the review deals with the advantages and differentiation of the Type II inhibitors focusing on *Address correspondence to this author at the Galápagos NV., Industriepark Mechelen Noord; Generaal De Wittelaan L11 A3; B-2800 Mechelen, Belgium; Tel: +32 15 342 900; Fax: +32 15 342 901; E-mail: javier.blanc@glpg.com 1871-5206/13 $58.00+.00 the recent developments made in the last few years. This review is set with the aim of providing the reader a strong background on Type II inhibitor differentiating them from other types of kinase inhibitors. Moreover, the point that makes this review exceptional is that it highlights the potential problems that can be generated by Type II inhibitors and present their solutions applied in literature to tackle them. In addition, this review reports all those Type II compounds that have either been approved by the FDA, or are in pipelines of different companies, demonstrating a ray of hope to bring creativity in spite of difficulties. 2. DIFFERENT TYPE OF TYROSINE-KINASE INHIBITORS 2.1. Type I Inhibitors This type of molecules represents ATP-competitors that exhibit an interaction with the catalytic site of the phosphorilated active conformation of kinases, mimicking the purine ring of the adenine moiety of ATP [4]. One to three hydrogen bonds with the protein are formed with the interaction between inhibitor and kinase in an area termed as ‘the hinge region’. Extra interactions can also be observed at adjacent hydrophobic regions. The hydrophilic region of the enzyme occupied by the ribose moiety of ATP may be exploited for maximizing the solubility of the compounds [7]. Ten Type I kinase inhibitors for the treatment of cancer have recently been honoured with an approval by the FDA namely gefitinib, erlotinib, dasatinib, sunitinib, lapatinib, pazopanib, vemurafenib, ruxolitinib, crizotinib, and bosutinib (Fig. 1). Discovery of second generation Type I kinase inhibitors comes up with several challenges. Since the targeted ATP pocket is conserved through the kinome, Type I inhibitors show a tendency for low kinase selectivity, thereby increasing the potential for offtarget side effects [8]. For example, on the basis of research performed on gene-targeted and/or transgenic mice, 32 kinases of relevance in the heart and vasculature have been identified. Inhibition of these kinases could be a concern for causing potential deterioration in cardiac function [9]. Hasinoff et. al. analyzed 7 FDA-approved tyrosine kinase inhibitors against a panel of 317 kinases in order to correlate binding selectivity scores with kinase inhibitor-induced damage to neonatal rat cardiac myocytes, by measuring the increase of lactate dehydrogenase (LDH) levels. On the basis of this analysis, the authors have reported a correlation between the lack of kinase selectivity and myocyte damage in vitro. Therefore, inhibition of a broad number of kinases is found quite likely to cause myocyte damage. This provides potential to researchers for predicting the clinical cardiotoxicity of a molecule [10]. © 2013 Bentham Science Publishers
  2. 2. 2 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0 Table 1. Blanc et al. Comparison Between the Different Types of Kinase Inhibitors Type I Type II Type III Type IV Covalent Inhibitors Type of binding Reversible Reversible Reversible Reversible Irreversible Binding site ATP site ATP site and DFG pocket Allosteric (by ATP pocket) Allosteric (substrate binding domain) ATP site ATP-competitive Yes No No No No Selectivity Low High Very high Very high Low O N N N O O HN O O O N N O N HN N Cl H N S HO Dasatinib Sprycel (BMS-2006) Multitarget Erlotinib Tarceva (Genentech/Roche-2005) ErbB-1 F N HN Cl Gefitinib Iressa (Astrazeneca-2003) ErbB-1 N N O N N N H O HN S O HN S O F N NH 2 F Cl N N H N Ruxolitinib Jakaf i (Incyte-2011) JAK1/2 HN N Cl N N F N H NH2 Pazopanib Votrient (GSK-2009) VEGFR family, PDGFR, cKIT N N N S O CN O Vemurafenib Zelboraf (Roche-2011) B-Raf O HN Lapatinib Tykerb (GSK-2007) ErbB-1/ErbB-2 O N F O O N Cl F N Sunitinib Sutent (SUGEN/Pfizer-2006) H VEGFR family, PDGFR Cl N HN N H O N N N O Crizotinib Xalkori (Pfizer-2011) ALK/Met N O N O CN HN Bosutinib Pre-registration (Pfizer) Bcr-Abl, Src O Cl Cl Fig. (1). Chemical structure of Type I kinase inhibitors approved by the FDA: generic name; brand name; company name; year of approval by the FDA; and inhibited kinase/s. However, the in vitro findings do not fully match with the clinical data as in the case of dasatinib, who reported a high increase in LDH levels in vitro [10], but exhibited a low level of cardiopathy during clinical studies. On the other hand, lapatinib, a compound presenting a high selectivity kinase inhibitor profile and the lowest increase of LDH in vitro, was reported to cause left ventricular ejection fraction (LVEF) depression in patients during clinical studies [11]. Overall, the majority of the approved agents are in fact well tolerated in monitored patients from a cardiac safety perspective [9]. Other issues are yet to be discussed such as tolerance of the compounds to mutations, since modifications in the ATP pocket are likely to bring a decline in the activity of the inhibitor [12]. 2.2. Type II Inhibitors This type of molecule represents a non-ATP-competitor that interacts with the catalytic site of the unphosphorilated inactive conformation of kinases, exploiting new interactions inside the lipophilic pocket derived from the change of conformation of the phenylalanine residue of the DFG N-terminal loop (Fig. 2). The inhibitor reversibly interacts with the kinase that results into the formation of one, two or three hydrogen bonds with the protein in the ‘hinge region’ and also causes extra interactions in the open DFG-pocket. These new extra lipophilic interactions with the DFGpocket confer Type II inhibitors a high degree of selectivity towards other undesired kinases. These interactions cannot occur in the phosphorilated activated form of the kinase (Fig. 2: binding comparison of dasatinib, Type I inhibitor, and imatinib, Type II inhibitor, with Bcr-Abl). The advantages and differentiation of the Type II inhibitors have been further discussed in a later section (Section 3). 2.3. Type III or Allosteric Inhibitors These molecules bind outside the catalytic domain of the kinase, in regions that are involved in the regulatory catalytic domain modulating the activity of the enzyme in an allosteric manner. A high degree of kinase selectivity is exhibited because of the exploitation of binding sites and regulatory mechanisms that are unique to the target. Additionally, allosteric modulators can provide subtle regulation of kinases controlled by multiple endogenous factors, something not easily performed with ATP-competitors [15]. A new class of 4, 6-disubstituted pyrimidines (GNF-2 and GNF-5) that selectively inhibits Bcr-Abl dependent cell proliferation was introduced by Gray and co-researchers. This is particularly found to be significant for GNF-2 which does not inhibit c-Abl kinase in vitro (Fig. 3). Docking, NMR, X-ray
  3. 3. Type II Kinase Inhibitors Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0 N N N N H N HN HO N N N S Dasatinib Cl H N N H N O Imatinib O 3 N N Fig. (2). Overlay complex of dasatinib and imatinib with Bcr-Abl. Note the modification of conformation of the Phe382 of the DFG motif (highlighted with a circle): the conformation of Phe382 (2GQG) in the complex of activated form of Bcr-Abl/dasatinib (black structure) would not allow the binding of imatinib (grey structure). Conversely, dasatinib would be able to bind to the inactive form of the kinase due to the conformation of Phe382 (1IEP) [13, 14]. O F3CO NH R NH N N R: -H; GNF-2 -(CH 2)2OH; GNF-5 H N O O H N O H N F N Selumetinib (AZD6244) N HO Cl H N PD 0184352 (CI-1040) HO O O H N O H N OH F I HO Cl F PD 0325901 F O H N O H N N Br ARRY-509 F I F HO F O H N O H N F Br I O G-894 HN N Fig. (3). Allosteric inhibitors: GNF-2, GNF-5, PD 0184352 (CI-1040), PD 0325901, selumetinib (AZD6244), ARRY-509 and G-894. crystallography, mutagenesis and hydrogen-exchange experiments all show consistency with binding of these molecules to the myristate-binding site located near the C-terminus of the kinase domain, resulting in allosteric inhibition. This binding is thought to induce a bent conformation of the -I helix that facilitates the stabilization of an inactive form of Bcr-Abl. Mutations in the ATPpocket terribly affect the inhibitory activity of these molecules. In contrast to imatinib, GNF-2 shows strong IL-3 reversible antiproliferative and apoptotic effect on mutants E255V and Y253H. On the other hand, like imatinib, this family also does not exhibit any activity towards cells expressing G250E, Q252H, F317L and T315I Bcr-Abl mutant. Unsurprisingly, mutations at the myristate pocket (A337N and A344L) report a detrimental impact on the activity of GNF-2 and GNF-5. Encouragingly, combination therapy of ATP and non-ATP competitors nilotinib and GNF-5 reported complete disease remission in a T315I mutant murine bone-marrow transplantation in vivo model [16, 17]. Scientists from Pfizer discovered a set of benzhydroxamate allosteric MEK inhibitors that stabilize the kinase in the inactive conformation of the enzyme (Fig. 3; PD 0184352 (CI-1040), and PD 0325901) [18, 19]. These compounds were found to present a higher selectivity towards MEK and non-ATP and ERK-competitive. Crystal structures of MEK1 and MEK2 (closely related, dualspecific tyrosin/threonine protein kinases) with PD 0184352 reported the presence of a unique inhibitor-binding pocket adjacent but not overlapping with the cMgATP-binding site within the interlobal cleft of the kinase, explaining the non-competitivity with ATP. A low sequence homology with other kinases, explaining higher selectivity of these inhibitors was also observed at this
  4. 4. 4 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0 A) Blanc et al. B) PD318088 Val127 I Ser212 F F H O Lys97 O Adenosine O P O O O P O O O O P Mg N F Br NH HO O O HO Fig. (4). Mode of binding of PD318088 with MEK1 at the active site, close to the hinge. A) Model structure of the molecule with the kinase; B) schematic drawing of the H-bond interactions of PD318088 with the amino acids of MEK1 [20]. region. SAR observations revealed the orthogonality of the aniline ring towards the anthranilate ring, directing the aromatic ring towards Phe209 in the hydrophobic pocket; the iodine was found quite favourable to electrostatically interact with Val127; the anthranilate phenyl ring was found to be present in less hydrophobic pocket; and the 4-fluorine reported a formation of a critical H-bond with Ser212 [3, 20, 21] (Fig. 4). PD 0184352 advanced into Phase II but could not present complete efficacy because of the insufficient systemic exposure (oral bioavailability in human: 5%) low solubility and rapid metabolism [19]. Better physical properties were exhibited by PD 0325901 as compared to its predecessor, and therefore having better systemic exposure (oral bioavailability in human: >30%), but the compound was retrieved from Phase I because of ocular toxicity concerns in patients. Understanding the SAR and the chances offered by the pharmacophore for MEK, has encouraged the development of new series of compounds. Selumetinib (AZD6244) and ARRY-509 were developed by the researchers of Array Biopharma with the replacement of the central anthranilate phenyl ring by a benzimidazole and a pyridine respectively [3]. Genentech replaced the central ring with the help of a benzopyrazole (G-894) and other heteroaryls, demonstrating the versatility of the pharmacophore [22]. 2.4. Type IV or Substrate Directed Inhibitors These kinase inhibitors are reported to be small molecules that present a reversible interaction outside the ATP pocket, in the kinase substrate binding site, but not competing with ATP. Since this area being unique for the substrate, it forces this type of compounds to potentially present a high degree of selectivity. ON012380 is a potent non-ATP competitive inhibitor of BcrAbl (10.0 nM) (Fig. 5). This molecule is likely to target a site of the natural substrate of the enzyme, such as Crk. Furthermore, imatinib and ON012380 were found to synergistically inhibit wild-type Bcr-Abl that suggests a binding of these two compounds to different sites on the enzyme. ON012380 was found to be promising for OMe MeO OMe O O S OMe NH CO 2H ON012380 Fig. (5). Substrate directed inhibitor ON012380. inhibition of all the imatinib-resistant mutants of Bcr-Abl that were tested such as T315I (7.5 nM) [23]. 2.5. Covalent Inhibitors These kinase inhibitors directly target a catalytic nucleophile within the active site of the enzyme, and an irreversible covalent bond is formed. This ‘suicide’ inhibition takes place via trapping of a solvent-exposed cysteine residue either by SN2 displacement of a good leaving group or by reacting with a Michael acceptor incorporated within the inhibitor [4, 24, 25]. The structural similarity of these compounds with Type I inhibitors, and the irreversibility of the inhibition are found to cause the inhibition of kinases with high Km values for ATP, by shifting the equilibrium between the free and the inhibitor-bound fraction (Fig. 6). This inhibitors exhibit a plethora of advantages as the one being the long dissociation half-lifes, which maximizes the efficacy beyond the clearance of the inhibitor, reduces the drug exposure and minimizes off-target effects [26]. However, the potential irreversible modification of on-target or off-target proteins and the potential lack of kinase selectivity are yet to be defined. For addressing the latter, researchers have targeted non-conserved cysteines in the kinome. For refinement of this approach, a basic functionality is introduced adjacent to the electrophilic centre to speed up bond formation by activating the cysteine. Adjustments in the linker that position the electrophilic centre close to the cysteine thiol, and modifications in the original scaffold itself, can also play a key role in optimizing selectivity and targeting inactivation rate. Irreversible inhibitors generated from such an optimization program are known as rapid kinase inhibitors that show a high degree of selectivity [27]. Recently, Winssinger and colleagues first time targeted a cysteine that is found to appear at the time when the kinase adopts the inactive DFG-out conformation, by arming the Type II inhibitor imatinib with an electrophilic centre (Fig. 7). Among the kinases that are likely to adopt the required conformation for accommodating the imatinib pharmacophore, only cKIT and PDGFRs, possess a suitably positioned cysteine residue at the beginning of the catalytic loop (Cys 788 and Cys814 respectively). Interestingly, the authors were able to discriminate with their inhibitors the selected kinases amongst others, such as Bcr-Abl [26]. 3. TYPE II INHIBITORS While ATP-competitive kinase biochemical assays of highly active recombinant kinase domains led the discovery of most early Type I inhibitors, serendipity led to the discovery of a second type of kinase inhibitors that was later shown to specifically bind an inactive conformation of the kinase domain. In this so called ‘DFGout’ conformation, the side chain of the phenylalanine residue of
  5. 5. Type II Kinase Inhibitors Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0 5 O O N O N N H O N CN N O N N H HN Neratinib O O N CN N N H HN Pelitinib N O HN Afatinib F F Cl Cl Cl O N O N O N O N N HN N N N N N N H HN O Canertinib O N HN NH 2 Dacomitinib F F Cl Cl PCI-32765 O Fig. (6). Cysteine-targeted kinase inhibitors currently in clinical development. N Cl 1 H N O H N Cl N H N O N N R3 H N 2 O H N N N H N R2 N H N O 3: R2 : -Me; R3: -H 4: R2 : -H; R3: -Me O H N N N Fig. (7). Compounds developed by Winssinger’s lab to target a cysteine that is available when the kinase adopts the inactive DFG-out conformation. the DFG N-terminal motif of the kinase activation loop becomes exposed and penetrates the ATP binding cleft, which results in the stabilization of the inactive and unphosphorilated form of the kinase, thereby, opening a hydrophobic pocket proximal to the kinase “gatekeeper” residue. Since canonical ATP binding site of activated kinases does not involve any such feature, this pocket is conserved to a lesser extent across the kinome and hence promises better prospects for the rational design of selective inhibitors [7, 28]. The earliest and archetypal Type II kinase inhibitor drug imatinib (STI-571) was classically optimized from a phenylaminopyrimidine screening hit with broad spectrum kinase inhibitory activity into a selective Bcr-Abl inhibitor using only kinase inhibition assay information (Figs 8, 9 and 10) [29]. A posteriori from the X-ray structure of an imatinib fragment in murine Bcr-Abl [30] was found to be beneficial in deciphering the highly unusual binding mode and was later confirmed with the full-size compound [31]. Approximately, six hydrogen bonds with the Bcr-Abl kinase domain were formed by imatinib in the latter structure: one between the pyridine nitrogen and the backbone NH of Met318 in the hinge region; another between the anilino NH group and the side chain hydroxyl of the “gatekeeper” residue Thr315; a pair of concerted Hbonds between the amide linker and both Glu286 of the C helix and the Asp381 backbone NH of the DFG segment. Type II inhibitors exhibit the high conservation of this distinctive H-bond pattern between the inhibitor and the glutamic and aspartic acids of the kinase. An interaction is found to be present between the protonated methylpiperidine tail group of imatinib, while partially solvent-exposed, and the backbone carbonyls of both Ile360 and His361. Imatinib is also reported to involve in extensive hydrophobic contacts with the Bcr-Abl kinase such as notable stacking interactions between the pyrimidine ring and both the Tyr253 of the collapsed P-loop and Phe382 of the DFG segment. A series of hydrophobic residues (Met290, Ile293, Leu298, Leu354, Val379) line the DFG-out pocket that is occupied by the imatinib benzamide group by replacing the displaced Phe382 side chain. Interestingly, imatinib has also been shown to adopt a Type I binding mode in Syk, acting as a weak inhibitor (IC50 > 10 M) [32]. Solved X-ray structure of imatinib in Bcr-Abl has helped in the formulations of general Type II kinase design guidelines. The principal strategy, known as hybrid-design, is the combination of a hinge binding group with a DFG-out pocket targeting hydrophobic motif for exploring the high potency of some Type I platforms and the selectivity potential promised by Type II inhibitor. Bond between the hinge binding and DFG-out targeting motifs can accurately be achieved by moieties that preserve the intricate Hbond network involving the conserved glutamic acid of the -C helix and aspartic acid of the DFG segment as it plays a necessary role in stabilizing the inactive kinase conformation. Thus, the presence of an amide or urea in the molecule has been validated as a hallmark of Type II inhibitors. In an additional approach, a hydrophobic substitution may be introduced for occupying the pocket formed by the shift of phenylalanine from the DFG motif [7]. A recent work by Molteni and co-workers reported the application of the hybrid-design method for discovering GNF-5837 (Fig. 9), a selective TRK inhibitor that exhibited its efficacy in rodent models suffering from cancer tumour. A structure similar to the Type I inhibitor sunitinib, has been combined with a tail portion present in Type II inhibitors by the authors. This tail containing urea in its centre is interacted with the kinase, and a terminal 2fluoro-5-trifluorophenyl hydrophobic moiety to occupy the place of the phenylalanine of the DFG motif flipped into the ATP pocket, for the stabilization of the inactive form of TRK kinase [34].
  6. 6. 6 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0 A) Blanc et al. B) Imatinib (STI-571) Ile360 His361 Met318 Thr315 Glu286 N H N N N N H N H N O Asp381 Fig. (8). Mode of binding of imatinib with Bcr-Abl. A) Model structure of the molecule with the kinase; B) schematic drawing of the H-bond interactions of imatinib with the amino acids of Bcr-Abl [30, 33]. Generally, Type II kinase inhibitors as compared to Type I kinase inhibitors are more likely to present higher selectivity towards target along with lower dissociation rate constant in biochemical activity, and a profound impact on cellular activity. Whereas the exploitation of the hydrophobic DFG-out pocket results in the production of molecules with high MW and clogP, which present detrimental consequences for druggability. Finally, the increase in drug resistance that may be caused by the mutations on the hinge region or on the “gatekeeper” of the targeted kinase is reported to reduce the pharmacological effect of the molecule. 3.1. Selectivity As discussed earlier, the identification of those molecules has greatly been emphasized which are found to exhibit higher selectivity towards a specific target for minimizing side effects and toxicity. Type II inhibitors in comparison to those of Type I present a higher selectivity because of their ability to recognize structurally distinctive regions of the active cleft outside the highly conserved ATP binding site that can only be reached in the inactive form of the kinase. Moreover, subtle modifications of the regions of the inhibitor interacting with the DFG-out pocket are found quite likely to enhance this selectivity [35, 36]. A total of 72 kinase inhibitors against 442 kinases have been introduced by Treiber and Zarrinkar, covering more than the 80% of the human kinome. In comparison to Type I inhibitors, those of Type II have been validated to be more promising. This observation highlight a consistency with the general assumption that the inactive conformation preferred by Type II inhibitors is more kinase-specific than an active conformation that can accommodate Type I inhibitors. However, the data also reported a large number of other Type II inhibitors that exhibit a lower degree of selectivity, and indeed a small number of Type I inhibitors being quite selective. Therefore, it becomes clear that selectivity of inhibitors does not depend on their type. A common theme for the most selective compounds, regardless of inhibitor type, is their structural features or kinase conformations which are exploited for distinguishing the target kinase from other kinases [8]. Another rationale for the observed high selectivity of some Type II inhibitors, is that not all kinases have the appropriate flexibility to adopt the DFG-out conformation [37]. Structural studies with Aurora-A and Aurora-B demonstrated the extensive state rearrangements observed by the protein during activation probably caused because of the high degree of flexibility of these enzymes. This property of the Aurora kinases may be exploited by the inhibitors being able to stabilize the inactive conformation by promoting hydrophobic collapse around the compound. These conformation changes are considered unlikely to be tolerated in other kinases lacking the same degree of flexibility [38]. Moreover, the selectivity profile of the desired molecule can be tuned by the exploitation or avoiding of extra interactions around the hinge. For example, masitinib is a molecule in which the central pyrimidine of imatinib has been replaced by a thiazole (Fig. 9). Interestingly, Hermine et al. observed a relative selectivity of masitinib for cKIT versus Bcr-Abl 10 fold higher than for imatinib. Docking of masitinib and imatinib in these kinases showed the involvement of pyrimidine ring of imatinib in a hydrogen bond network for conserving water molecules around the DFG motif of Bcr-Abl interaction that was not observed in cKIT. This observation helps to explain the selectivity of masitinib for cKIT, avoiding the potential cardiotoxicity of imatinib related to Bcr-Abl inhibition [39]. Whilst considering selectivity as a promising tool for reducing side effects and toxicity, multiple kinase inhibitions have been validated as therapeutically alternative approach. Thus, in multitarget drug discovery (MTDD), the approach of inhibiting two or more targets simultaneously with one chemical agent to avoid activation of alternative signalling pathways is considered to be promising. The treatment of multi-kinase inhibitors (MKI) with a multiple activity profile restricted to cancer-relevant protein kinases is highly acclaimed for curing malignant disorders, by presenting a complementary effect [37]. Moreover, multi-kinase inhibition of a number of different kinases involved in cancer may be quite effective against different kinds of tumours (Tables 2 and 3). For instance, the kinases such as Bcr-Abl, cKIT and PDGF-R involved in cancer are inhibited by imatinib. Imatinib since its approval by the FDA in 2001, has received 10 different disease indications (Table 2) [40]. Sorafenib is reported as a bis-aryl urea derivative that results from an initial HTS for Raf-1 [41] (Table 2, Fig. 9) followed by subsequent SAR development [42]. This oral anti-tumour agent approved for RCC and HCC, is found to present a multikinase activity profile (B-Raf, VEGFR family, PDGFR, cKIT and FLT-3) (Table 2). Inhibition of these kinases results in a dual effect the one as tumour suppression and the other being neovascularisation inhibition [43, 44]. Regorafenib (Table 2, Fig. 9), a molecule differed from sorafenib only because of the presence of a fluorine atom in the centre phenyl ring, is also considered as a multitarget kinase inhibitor (VEGFR family, PDGFR- , cKIT, B-Raf and RET). This molecule having a complementary inhibitory profile is found to be quite efficient for controlling tumour neo-angiogenesis, vessel growth and metastasis [45], presenting a synergic effect on cancer treatment [46]. In addition, combined inhibition of several
  7. 7. Type II Kinase Inhibitors Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0 CF3 N N H N N H N O O O N N H N Imatinib (STI-571) CF3 O Cl N N H O Cl N H 7 O N H F O N H N N H Regoraf enib (BAY 73-4506) Soraf enib (BAY 43-9006) N O N CF3 HN O HN O HN N H N N H N H Motesanib (AMG-706) O O N H N O N N H N N S O N H N N O N N O O N O N N N Tandutinib (MLN-518) O O O N RAF265 F3C AAL993 O N N N N CF3 N H N H N H Quizartinib (AC220) S N H F Masitinib (AB-1010) O N N H Tivozanib (AV-951 or KRN951) CF3 O N O N H Cl N H H2N NH N N H O O Linif anib (ABT-869) F N H N H N H N H GNF-5837 O O N N N N H O N H Doramapimod (BIRB-796) Fig. (9). Different Type II kinase inhibitors. pro-angiogenic pathways may prevent resistance or prolong progression-free survival. Indeed, adaptive responses by the tumour and the vasculature to anti-VEGF therapy have been postulated [47]. A similar approach for tivozanib (AV-951 or KRN951) [48, 49], and linifanib (ABT-869) has been adopted by other authors [50]. AAL993 (Fig. 9) is known as a hybrid-design Type II inhibitor derived from the Type I inhibitor PTK787 (vatalanib) [51]. It is considered as a potent inhibitor of VEGFR family that was identified after main optimization of an anthranilamide series [51, 52]. The lack of selectivity of AAL993 within the VEGFR family, located in vascular endothelial cells (VEGFR-1 and -2) and lymphatic vessels (VEGFR-3) [45], is found likely to present some advantage. Inhibition of VEGFR-kinase is found quite promising to suppress tumour growth, vascularisation and metastasis without affecting normal tissue [52]. The kinase inhibitor motesanib was identified after a subsequent lead optimization (Fig. 9) [53]. Motesanib is reported to inhibit the inactive state of five kinases linked to the pathogenesis of several human cancers which are named as VEGFR1, VEGFR2, and VEGFR3; cKIT and PDGFR. The in vivo activity of motesanib is generally attributed to the broad activity against all VEGFRs tested, such as VEGFR1, VEGFR2, and VEGFR3. VEGFR1 has been shown to mediate the recruitment of endothelial precursor cells to areas of active angiogenesis, whereas VEGFR3 has been reported to play a remarkable role in lymphangiogenesis. Moreover, the stabilization of nascent vessels involves associations with pericytes, a process mediated by PDGFR. This small-molecule multi-kinase inhibitor targeting VEGFRs has shown promising clinical activity against various solid tumours, including GIST, melanoma, and RCC [54]. Thus, desired selectivity may be refocused towards functional selectivity, where the anticancer compound inhibits only those kinases that are directly involved either in the pathological process or in the pathological pathway of the disease to produce a beneficial synergistic effect. 3.2. Activity: Biochemical vs Cellular Type II inhibitors are quite likely to exhibit a low association rate constant (kon), but a profoundly lower dissociation rate constant (koff). This can result in a higher residence time compared with Type I inhibitors, providing a potential benefit of extended kinase inhibition. The phenomenon of low koff may be attributed to the extra hydrogen bonding and higher lipophilicity of these molecules may be the reason behind this phenomenon of low koff [55]. Doramapimod (Fig. 9), an inhibitor for p38- (serine/threonine kinase [56]), exhibits a slow binding behaviour, whereby its activity maximizes with the time (IC50 value reduces from 97 nM to 8 nM after incubating for 2 hours) Moreover, the residence time for this molecule is calculated to be 23 hours. The high contribution of the very low koff value is reported to cause this high value. The in vivo efficacy is affected by potential impact presented by this slower dissociation [57]. Different binding affinities and residence time at each of the different kinases inhibited can be presented by multikinase inhibitor as an added complexity which is reported to affect selectivity and
  8. 8. 8 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0 Table 2. Blanc et al. Molecules that are Either FDA Approved or in Clinical Development Generic Name Internal Name Brand Name Company Kinase Target • STI-571 Gleevec (USA) Glivec (EU) Novartis International AG • cKIT • Approved by the FDA: Bcr-Abl PDGFR- • Imatinib Indication Disease or Clinical Study Status for Cancer PDGFR- • Nilotinib AMN107 Tasigna Bcr-Abl and mutants (except T315I). cKIT • ASM associated with cKIT. Approved by the FDA: • CML-CP and CML-AP, intolerant/resistant to imatinib. Phase III clinical studies: PDGFR- • MDS/MPD, HES/CEL associated with PDGFR- ; • • GIST: associated with cKIT and PDGFR- ; • • Novartis International AG CML and ALL associated with Brc-Abl; • PDGFR- • cKIT melanoma; • GIST: associated with cKIT and PDGFR- . Approved by the FDA: • • BAY 43-9006 Bayer Schering Pharma AG B-Raf and V600E mutant • RCC; VEGFR family • HCC. • PDGFRcKIT FLT-3 Phase II clinical studies: • VEGFR family/TIE2 Phase III clinical studies: • B-Raf and V600E mutant • PDGFR- • cKIT • VEGFR family • cKIT • RCC; • PDGFR • Breast cancer and CRC. • VEGFR • PDGFR • CSF1R • Nexavar • • Sorafenib cKIT, V559D, D816V and D814V mutants Phase III clinical studies: • • Regorafenib Tivozanib Motesanib BAY 73-4506 AV-951 KRN951 AMG 706 - - - Bayer Schering Pharma AG AVEO Pharmaceuticals, Inc. and Astellas Millennium Pharmaceutical (Takeda) and Amgen, Inc. • NSCLC, thyroid cancer and breast cancer. Breast cancer, ovarial/peritoneal cancer and CRC. CRC and GIST. Phase II clinical studies: • Cancer. Phase III clinical studies: Phase III clinical studies: • First-line non-small cell lung cancer. Phase II clinical studies: • First-line breast cancer. Phase III clinical studies: Masitinib AB-1010 - AB Science • PDGFR • Pancreatic cancer; • GIST; Phase II clinical studies: • drug efficacy in vivo. A total of 15 different kinases were inhibited by Sorafenib. The longest residence time for Ckit was calculated to be (811 minutes) followed by CDK8/CycC and B-Raf (576 and 568 minutes respectively). Medium residence times for DDR2 and DDR1 were calculated to be (45 and 24 minutes respectively). Residence times for other targets such as TAOK3 and TIE2 were calculated to be lesser than 2 minutes. This difference in residence time that is also reported to be the same for doramapimod can be affective in vivo. Up to 50% of DDR1 and 100% of CDK8/CycC are blocked by Sorafenib after 5 hours; after 7 hours, DDR1 is no longer blocked while CDK8/CycC activity still gets inhibited by 90%. When the inhibition of DDR1 and cKIT is compared, residence time starts to act even more strikingly. However DDR1 is a high-affinity target and cKIT being a low-affinity target, both are inhibited to an equal extent 4 hours post Cmax. After 7 h when, DDR1 is no longer inhibited, the low-affinity target cKIT is still blocked by 50%. In the same way, also the inhibition of CDK8/CycC and cKIT becomes likely to draw level after 18 hours [58]. Multiple myeloma. Finally, Type II inhibitors while targeting the inactive DFG-out state of the kinase, with a KM,ATP value higher than the corresponding value for the active DFG-in state, have to face weaker competition from cellular ATP, which may enhance activity in vivo. Indeed, even though these compounds may be ATP competitive, they might act primarily by locking the equilibrium switch between conformational states in a way that prevents kinase activation, rather than directly inhibiting it [36, 59]. 3.3. The Effect of MW and logP on Solubility and Cell Penetration Many other selective and potent compounds can be identified if the peculiarities of the hydropholic DFG-out pocket are exploited. As described, however, this exploitation results into the production of molecules with high MW and logP but exhibiting the potential of limited solubility, cell penetration and PK properties. For oral administration, problems can be created in late phases of drug discovery by this drawbacks [60, 61]. However, evidence to date suggests a slight difference between kinase inhibitors properties and
  9. 9. Type II Kinase Inhibitors Table 3. Generic Name Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0 Molecules that are Either FDA Approved or in Clinical Development Internal Name Brand Name - Abbott Indication Disease or Clinical Study Status for Cancer PDGFR Phase III clinical studies: • VEGFR family • AML; • cKIT • RCC; • ABT-869 Company Kinase Target • Linifanib 9 FLT3 • Breast cancer and CRC. Phase II clinical studies: Quizartinib AC220 - Ambit Biosciences • FLT3 • • cKIT Phase I clinical studies: • AML. GIST. Approved by the FDA: • AP24534 Iclusig ARIAD Pharmaceuticals • • cKIT Phase I clinical studies: • PDGFR- • • Ponatinib Bcr-Abl and mutants (including T315I). cSRC, FGFR, VEGFR2 and Lyn Preclinical studies: CML and Ph+ALL associated with Brc-Abl Pharmacological resistance. AML. Angiogenesis and solid tumours. Phase II clinical studies: • • Lyn Phase I clinical studies: PDGFR- • FLT3 • cKIT • Bcr-Abl and mutants (including T315I). Phase I clinical studies: • CML, refractory/intolerant to imatinib/nilotinib. • FLT3, TIE2 and TRKA • ALL and AML. B-Raf and V600E mutant • VEGFR2 Phase I clinical studies: • PDGFR- • • CytRx Corporation Bcr-Abl • - • • Bafetinib INNO-406 NS-187 cKIT • Tandutinib - - Millennium Pharmaceutical MLN518 DCC-2036 RAF265 - - Deciphera Pharmaceuticals LLC Novartis International AG the ones of “non-kinase-target” oral drugs. Thus small molecule clinical compounds targeting kinases in comparison to other compounds in the same phase of development are reported to exhibit significantly higher MW and logP [62]. For oral administration in oncology, compounds such as imatinib, nilotinib (Fig. 10) and sorafenib can be purchased from the market available at doses of 400 mg qd, 300 mg bid and 400 mg bid respectively. These molecules have a high molecular weight and logP, especially nilotinib (MW: 529.18; logP(octanol-water): 4.9, 5.0) [63]. Nevertheless, strategies continued to be directed towards increasing solubility. A piperazinyl group in imatinib was introduced by Kuriyan and co-authors to increase the solubility compared with the parent compound. Target inhibition is not found to be drastically altered by this new solubilising substituent. It is likely to stand along a solvent accessible and partially hydrophobic groove on the back of the kinase left unfilled by imatinib variant [30]. The successor molecules such as ponatinib [64] or bafetinib are also found to follow this same philosophy [65] (Fig. 10). Alternative strategies may be utilized to introduce the solubilizing substituent into the hinge region or the region adjacent to the ribose pocket. This is the case for doramapimod (Fig. 9), where a morpholino substituent is reported to interact with the hinge, improving the physicochemical properties of the inhibitor for oral dosing [57]. B-CLL and advanced prostate cancer Brain cancer. Phase I clinical studies: • Solid tumours. Malignant melanoma. In the development of tandutinib (Fig. 9), Pandey and coworkers report a link between a solubilising 7-piperidinepropoxy group and a quinazoline derivative. This resulted in the production of a potent compound exhibiting optimal pharmacokinetic properties in the animal model, with an oral bioavailability of 50%. This compound was found to suppress the progression of disease in a FLT3-mediated leukemia mouse model, showing efficacy in a nude mouse model for CML [66]. Bhagwat and co-workers have also adopted a similar approach in the development of quizartinib (Fig. 9). They introduced a solubilizing morpholinoethoxy group on to the core ring interacting with the hinge. This led to the discovery of a novel series of highly potent and selective compounds with a significantly improved solubility and PK profile. Quizartinib was identified as one of the most potent and selective FLT3 kinase inhibitors of the series [67]. More drastic modifications have been explored. The presence of an amide or urea in the molecule was found to be necessary for the interaction of the glutamic and aspartic acid in the DFG-pocket. On the other hand, these functional groups are reported to reduce the solubility of the inhibitor. This drawback can be tackled by substitutions of these functionalities presented by bio-isosteres [68]. Ramurthy and co-workers replaced the urea of sorafenib and regorafenib by an aminoimidazole group, with the aim of improving the physicochemical properties of the B-Raf inhibitor. A
  10. 10. 10 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0 Blanc et al. First Generation Bcr-Abl inhibitors N N H N N H N O N N Imatinib (STI-571) Second Generation Bcr-Abl inhibitors CF3 CF3 N O N H N N H N N N N H N N H N O N N N N Bafetinib (INNO-406 or NS-187) Nilotinib (AMN107) Third Generation Bcr-Abl inhibitors CF3 N CF3 N O N O O N N N N N H N H N H O N H N F O N N R N NH O Ponatinib (AP24534) DCC-2036 N GNF-6; R: H N GNF-7; R: H N N CF3 N N H N N DSA8 H N N O H N O O N N N N N O N H NH N S HG-7-85-01 Fig. (10). Different generations of Bcr-Abl inhibitors. docking model of this bio-isostere showed a DFG-out induced conformation [69, 70]. RAF265 (Fig. 9), a member of this series has been brought to phase I/II clinical studies for melanoma, and its efficacy in both wild type and mutated V600E B-Raf melanoma has been validated by the recent data [71]. As with Type I kinase inhibitors, classical medicinal chemistry structure modifications, such as addition of ionizable or polar groups, reduction of logP or MW, addition of hydrogen bonds, disruption of molecular planarity or construction of pro-drugs, have helped to improve solubility of this type of the Type II compounds [72]. 3.4. Resistance for Type II Inhibitors Natural selection by tumour cells may present drug resistance during antineoplastic treatment. This selection can lead to a predominant colony of cells likely to neutralize the effectiveness of the treatment. Similar cancer cells can develop resistance mechanisms against kinase inhibitors. For example, 33% of imatinib patients are reported to develop resistance. Several mechanisms are responsible for this resistance which could also extend other kinase inhibitors: • Over-expression of p-glycoprotein efflux transporters through MDR-1 gene expression to increase active efflux across the cell surface and to reduce intracellular concentration of the compound [73]. • Over-expression of -1 acid glycoprotein to induce high plasma protein binding of imatinib, and therefore, reducing concentration of free fraction of the kinase inhibitor available to the cancer cell [74, 75]. • • • • Over-expression of metabolic enzymes such as prostaglandinendoperoxide synthase 1/cyclooxygenase 1 (PTGS1/COX1) which encodes the enzyme that metabolizes imatinib [76]. Activation of alternative biochemical signalling pathways to bypass the effect of the kinase inhibitor [77]. Amplification of the oncogene Bcr-Abl, with the subsequent increase of the production of Bcr-Abl [78]. Mutations in the primary structure of the kinase : These mutations are reported to generate a “conformational escape” [79], causing the destabilization in the equilibrium between the phosphorylated forms and unphosphorylated ones of the enzyme towards the active state [80]. Moreover, mutations around the ATP pocket are reported to alter the binding properties through which the inhibitor interacts, or introduces a new steric restriction [12, 78]. These two phenomena are reported to reduce the therapeutic activity of the inhibitor. There are different locations where transformations in the kinase can appear: Mutations in the P-loop and the activation loop, destabilizing the inactive form of the kinase in favour of the active state, the main consequence of which is reduced by the activity of those inhibitors that target the DFG-out pocket [81]; Mutations in the “gatekeeper”, the hinge and hydrophobic pocket, are modified either by the binding interaction network or by introducing steric clash. Such mutations in the “gatekeeper” introduce a bulky hydrophobic residue (Ile or Met). Consequently, a direct drop is observed on the binding strength, reducing the inhibitory effect [78]. These mutations have thoroughly been investigated in Bcr-Abl (T315I), cKIT (T670I), PDGFR(T674I), EGFR (T790M) and Src (T790M) [82, 83].
  11. 11. Type II Kinase Inhibitors For suppressing mutant resistance, researchers have recently come up with several strategies in drug design. These strategies include synthesis of more potent compounds, overcoming the impediments introduced by the mutations; stabilization of the inactive conformation of the kinase with a Type II inhibitor; design of new molecules by hybrid-design, or application of a combinatorial therapy of different anti-neoplasics. In the subsequent section these approaches are considered in turn [82]. 3.4.1. Synthesis of More Potent Compounds Nilotinib is considered as a Type II 2nd generation Bcr-Abl inhibitor (Fig. 6) that has been developed by rational drug design based on the crystal structure of a Bcr-Abl-imatinib complex to override imatinib resistance [30, 31]. This inhibitor was achieved for its high potency and selectivity towards Bcr-Abl, whilst maintaining a good pharmacokinetic profile [84, 85]. Similar H-bond interactions are exhibited by nilotinib as the ones presented by imatinib in the hinge and the “gatekeeper” regions. An amide inversion helps to maintain the same interactions as imatinib maintains with Glu286 and Asp381 of Bcr-Abl [86]. Crucially, the pendant N-methylpiperazine substituent present in imatinib was replaced by 3-methylimidazole. The imidazole shows less critical interactions with the C-terminal lobe as compared to the ones presented by directional H-bond of the cationic Nmethylpiperazine of imatinib under physiological conditions. This provides nilotinib with a less stringent induced-fit binding than the predecessor [87]. In addition, this replacement, combined with the introduction of a trifluoromethyl group, increases the clogP of the molecule [63]. A displacement of the binding contribution from the hinge region of imatinib to the lipophilic DFG-out pocket in nilotinib is causes by new hydrophobic interactions. These hydrophobic interactions are also reported to render greater flexibility to the protein surface [88]. The chemical modifications maximize the inhibitor activity towards wild type Bcr-Abl, and exhibit a higher tolerance for point mutations than imatinib. Moreover, nilotinib becomes more active against phosphorylated [79]/unphosphorylated Bcr-Abl, and most of the known imatinibresistant Bcr-Abl mutants, with the exception of T315I. A loss of an H-bond between Thr315 and the aniline; and a steric clash between the mutated, bulky Ile315 and the methyl group of the same aniline substituent can be the reason behind this latter exemption of T3I5I [84]. The DSA library, derived from a Tie-2 kinase inhibitor library, is a set of Type II 3rd generation inhibitors capable of inhibiting Bcr-Abl, c-Src, and Hck [89]. As structure is concerned, this library shows an acute similarity with imatinib. The presence of methoxy aniline and the triazine in DSA8 (Fig. 10) may result in the formation A) Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0 11 of extra H-bonds with the hinge region of Bcr-Abl by analogy with imatinib, resulting in a stronger inhibition [90]. Regorafenib was developed from a novel discovery program aiming to maximize the potency and drug-like properties within a well-established urea class. The compound in comparison to sorafenib is found to be more pharmacologically potent and is obtained by introducing a fluorine atom onto the centre phenyl ring (Fig. 5), leading to a similar but distinct biochemical profile [46]. 3.4.2. Overcome the Steric Clash Introduced by Mutation In the T315I mutation of Bcr-Abl, the incorporated isoleucine introduces a bulky sec-butyl group close to the “gatekeeper”, reducing the volume of the pocket around the “gatekeeper”, and as a result brings a decline in the activity of imatinib and nilotinib. Several approaches have been described to reset the activity by reducing this steric clash. Ponatinib is classified as a Type II 3rd generation inhibitor (Fig. 11) that strongly inhibits Bcr-Abl and 14 related mutants, including T315I [91]. The inhibitor was developed in an attempt to increase the selectivity profile of a DFG-in library hit (AP23464) [92]. By exploring the DFG-out pocket, the authors increased the selectivity profile [93, 94]. Interestingly, introduction of an acetylene linker was found to reduce the flexibility of the molecule. The increase in rigidity diminishes the steric clash with the “gatekeeper” T315I mutant, allowing more favourable Van der Waals interactions with Ile315, and Phe382 of the DFG motif. Moreover, activity is maximized due to the reduced entropy imposed through rigidification [64]. Using the same linear acetylene linker, Gray and co-workers synthesized a library of different Type II 3rd generation inhibitors that also exhibited strong activity against wt Bcr-Abl and T315I [95]. Conversely, in order to diminish the steric clash with the “gatekeeper” produced by the T338M mutation in c-Src, Rauh et al. introduced a more flexible 1,4-substituted phenyl element, being able to freely rotate to avoid a collision with the bulky gatekeeper side chain without disturbing the binding interactions formed by the rest of the molecule [83]. Finally, in the DSA-library (Fig. 10), no interaction is observed between the nitrogen of the 2-methylaniline and the “gatekeeper” of Bcr-Abl or c-Src (T315 or T338) but there is rotation of the metadiaminophenyl ring in the library compounds relative to imatinib. This leads to displacement of the linker amino group relative to the position in Bcr-Abl·imatinib or c-Src·imatinib complexes. This displacement avoids the steric clash initially expected to occur due to the bulkier isoleucine side chain in the T315I and T338I mutation. Loss of the H-bond to T338 in Src is compensated by increasing interaction with the hinge [90]. Ponatinib (AP24534) B) Met318 Ile360 His361 Asp381 N N N CF 3 Ile315 O N N H H N Glu286 Fig. (11). Mode of binding of ponatinib with Bcr-Abl (T315I mutant). A) Model structure of the molecule with the kinase; B) schematic drawing of the Hbond interactions of ponatinib with the amino acids of Bcr-Abl (T315I mutant) [64].
  12. 12. 12 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0 3.4.3. Design Drugs for the “Switch Control Pocket” Thereby, Stabilizing the Inhibitor-bound Type II Conformation with the Kinase in the Inactive Configuration, Even in the Face of Phosphorylation or Mutations Such as T315I, that Otherwise would Predispose the “Conformational Escape” of the Enzyme to the Active Conformation DCC-2036 (Fig. 10) is a Type II 3rd generation inhibitor, capable of inhibiting both the phosphorylated and unphosphorylated forms of Bcr-Abl wild type and T315I. The authors approached the inhibitor resistance due to “conformational escape”, using “switch control pocket” inhibition to stabilize the kinase in the inactive form. The molecule provokes an interaction shift from residues Arg386/Tyr393 present in the phosphorylated active state of BcrAbl, to a new interaction with the Arg386/Glu282 residues present in the unphosphorylated inactive state of the kinase. To achieve this, the quinoline nitrogen of DCC-2036 is reported to interact via an H-bond with Glu282 that is stabilized by the close presence of Arg386. The urea interacts with the Lys271-Glu286 salt bridge, and Asp381; whilst the carboxamide-substituted pyridine ring results in the formation of H-bonds with the hinge residue Met318. No interaction or steric clash is reported between the molecule and the “gatekeeper”, explaining the retention of potency against the T315I mutant [79, 96]. 3.4.4. Exploration of New Inhibitor Scaffolds The application of hybrid-design is validated as a promising approach for designing new inhibitor scaffolds [35], in which Type I inhibitors are linked with Type II inhibitor tails known to interact with the DFG-out pocket [7]. GNF-7 (Fig. 10) is classified as a compound derived from a set of Type II 3rd generation inhibitors capable of inhibiting the T315I “gatekeeper” mutant of Bcr-Abl [97]. On the basis of a hybriddesign, the authors combined derivatives of the Type I inhibitor PD173955 as a core scaffold for interacting them with the hinge, whilst exploring the DFG-out pocket through incorporating substituents at the 3-position resembling Type II inhibitors nilotinib and AAL993 [98, 99]. Co-crystallisation of another compound from the same series, GNF-6, with Bcr-Abl confirmed the presence of a pair of H-bonds in the hinge with Met318, and a pair of H-bonds between the amide and Glu286 and Asp381 with no interaction being observed with the “gatekeeper”. HG-7-85-01 (Fig. 10) is another early example of Type II 3rd generation inhibitor based on a hybrid-design. The compound selectively inhibits several kinases involved in cancer: Bcr-Abl, cKIT, PDGFR- and PDGFR- ; and the respective “gatekeeper” mutants: T315I, T670I, T674I/M and T681I. An X-ray crystal structure of the c-Src wt/HG-7-85-01 complex revealed two Hbonds in the hinge region with Met341 and Tyr340. Moreover, as seen previously with imatinib, in the DFG-out pocket, two H-bonds were found between the amide of the compound with Asp404 and Glu310 of the kinase; and a further interaction between the protonated nitrogen of the distal N-methylpiperazine and the backbone carbonyls of Val383 and His384 [100]. 3.4.5. Override the Interactions Affected by the Mutation Both imatinib and nilotinib utilise aniline as an H-bond donor for interacting with the T315 of the “gatekeeper” of the wild type Bcr-Abl. This H-bond is lost if a T315I mutant is present, drastically reducing the activity of the inhibitors towards the mutated kinase. Compounds such as ponatinib [64], DSA-library [90] or HG-7-8501 [100], eliminate this interaction with the “gatekeeper” as described above. To maintain high potent compounds, additional interacting contributions are required to diminish the loss of this Hbond. In the future, the use of crystallography and fragment based approaches may be quite promising for identifying such additional interactions. Blanc et al. 3.4.6. Combinatorial Therapies of Different Kinase Inhibitors with Complementary Inhibition Scope, or other Classical Agents to Obtain an Additive/Synergistic Effect Combinatorial therapies or ‘cocktails’ of selective protein kinase inhibitors, with either other targeted agents or conventional chemotherapy, represent an emerging therapeutic concept for preventing or overcoming resistance in human malignancies. These combinatorial approaches are found to be more flexible in terms of target selection and therapeutic design than multi-targeted protein kinase inhibitors, because drugs with fundamentally different biological modes of action can be co-administered at different ratios relative to each other and according to variable time schedules. However, more effort are needed to determine the optimal doses that are both efficacious and well-tolerated by the treated patients [82]. The Japan Adult Leukemia Study Group (JALSG) combined imatinib with intensive traditional chemotherapy in a Phase II study. The authors obtained complete remission for the majority of patients that were diagnosed Bcr-Abl-positive ALL without an increase in toxicity [101]. Another approach of drug cocktail is combination of complementary Type I and Type II kinase inhibitors with an overlapping profile of resistance mutations in vitro. Deininger and co-workers compared dual combinations of imatinib, nilotinib, and dasatinib, to determine the efficacy and resistance of the cocktail against N-ethyl-N-nitrosourea-exposed Ba/F3-p210Bcr-Abl cells. Interestingly, combination of two potent inhibitors, dasatinib (Type I) and nilotinib (Type II), at different low concentration, resulted in the elimination of mutations except the T315I mutant. Since the nonhematologic side effects of nilotinib and dasatinib are not identical, patients with intolerance to either agent could potentially be managed with combinations at low doses, avoiding toxicity while maintaining full anti-leukemic activity [102]. In the case of T315I mutant treatment, this combination approach could be applied in the presence of 3rd generation of Bcr-Abl inhibitors. On the other hand, Bubnoff and co-workers proposed a combination of kinase inhibitors with a non-overlapping profile such as sunitinib (SU11248) (Type I) and sorafenib (Type II), to avoid resistance against FLT3 mutations. They came to this conclusion after analyzing individually these compounds against FLT3-ITD sitedirected mutagenesis and expressed in Ba/F3 cells [103]. 4. FUTURE PERSPECTIVES This review reports the development of the Type II kinase inhibitors, despite some evident limitations in cancer therapeutics, where they are emerging as components of standard-of-care therapy. Moreover, the increasing knowledge about the effects and efficacy, and about the existence and mechanistic basis for adaptive evasive resistance and intrinsic indifference, puts forward an exciting prospect for sustaining and improving the approach. For overcoming resistance, significant advances have already been made. In the future, we speculate the development of rationally designed inhibitors based on the Type II pharmacophore that will allow the generation of high-affinity inhibitors stabilizing the DFGout conformation of many other kinases for which this conformation has not yet been observed. In addition to serving as drug discovery lead compounds and as tools to investigate signalling pathways, these new Type II inhibitors will also facilitate the exploitation of structural plasticity of the kinase active site. The speed with which Type II inhibitors have been developed fuels optimism regarding the achievement of the final goal of controlling cancer.
  13. 13. Type II Kinase Inhibitors 5. CONFLICT OF INTEREST The authors declare that there is no conflict of interest in this review. 6. ACKNOWLEDGMENTS The authors want to pay their gratitude to Dr. Stephen Fletcher, Dr. Guy Van Lommen, Dr. Luc Van Rompaey and Dr. Laurent Saniere for proof reading. 7. ABBREVIATIONS ALK = Anaplastic lymphoma kinase ALL = Acute Lymphoblastic Leukemia AML = Acute Myeloid Leukemia ASM = Aggressive Systemic Mastocytosis ATP = Adenosine Triphosphate B-CLL = B-cell Chronic Lymphocytic Leukemia bid = bis in die (Latin: twice a day) CDK8 = Cyclin-Dependent Kinase 8 CEL = Chronic Eosinophilic Leukemia CHF = Congestive Heart Failure CML = Chronic Myelogenous Leukemia CML-AP = Chronic Myelogenous Leukemia-Accelerated Phase CML-CP = Chronic Myelogenous Leukemia-Chronic Indolent Phase CRC = Colorectal Cancer CSF1R = Colony Stimulating Factor 1 Receptor DDR1 = Discoidin Domain Receptor-1 DFG = Aspartic acid-Phenylalanine-Glycine DNA = Deoxyribonucleic acid ErbB-1/ErbB-2 = Subfamilies of Epidermal Growth Factor Receptor (EGFR) ERK = Extracellular signal-regulated kinase FDA = Food and Drug Administration FLT-3 = Fms-like Tyrosine Kinase 3 GIST = Gastrointestinal Stromal Tumor HCC = Hepatocellular Carcinoma HES = Hypereosinophilic Syndrome IC50 = Half Maximal Inhibitory Concentration IL-3 = Interleukin 3 IP = Intellectual Property JAK = Janus Kinase JALSG = Japan Adult Leukemia Study Group LDH = Lactate Dehydrogenase LVEF = Left ventricular ejection fraction MDR-1 = Multidrug Resistant Protein 1 MDS = Myelodysplastic Syndrome MKI = Multikinase Inhibitor MPD = Myeloproliferative Disorders MTDD = Multitarget Drug Discovery MW = Molecular Weight NMR = Nuclear Magnetic Resonance NSCLC = Non-Small Cell Lung Cancer PDGFR = Platelet-derived growth factor receptors PK = Pharmacokinetic Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 0 PTGS1/COX1 = qd RCC Syk TRK VEGFR = = = = = Prostaglandin-Endoperoxide Synthase Cyclooxygenase 1 quaque die (Latin: once a day) Renal Cell Carcinoma Spleen Tyrosine Kinase Tropomyosin Receptor Kinase Vascular endothelial growth factor 13 1/ 8. 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