Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
Target Family-Centric Privileged Structures:
unexploited opportunities
for medicinal chemistry
Gerhard Müller
Senior Vice ...
• Bayer Pharma AG
• AstraZeneca AB
• H. Lundbeck A/S
• Janssen Pharma NV
• Merck KGaA
• Sanofi
• UCB Pharma SA
300.000 com...
“What is clear is that certain “privileged structures“
are capable of providing useful ligands for more than
one receptor ...
Spirocyclic compounds:
 conformationally constrained  -TDS 
 frequently occur in natural products  protein binding 
...
J. Mol. Biol., 425, 662-677 (2013)
Convert GPCRs to soluble protein – biochemistry, biophysics, etc
G7 Therapeutics
5
Long...
O
N
O
O
Annelated ring systems – novelty analysis ongoing
Fsp3-rich carbon skeletons
annelation-constrained macrocycles
• ...
P. Furet et al. J. Comp.-Aid. Mol Des. 1995, 9, 465-472
P. Traxler, Exp.Opin. Ther. Patents 1998, 8, 1599-1625
N
NN
H
N
H
...
DFGin
DFGout
many „DFG-in-between“ ?
misleading terminology
A.P. Kornev, N. M. Haste, S. S. Taylor, L. F. Ten Eyck, Proc. ...
hydrophobic spine
comparison of intact and disrupted spines
O
N
N
H
O
N
H
N
H
O
Cl
CF3
intact R-spine disrupted R-spine (C...
Retro-Design Approach: B2F (back-to-front)
 Sets out with scaffolds rather than leads
 Disrupt hydrophobic spine
 Long ...
UPR as one major cause for neurodegeneration
AD disease mechanisms: UPR
ER
UPR (unfolded protein response):
• cellular str...
N
N N
NH2
N
O
N
CH3
F
GSK2656157 (IC50: 0.8 nM)
development candidate
WO2011119663A1
J.Med.Chem. 2012, 55, 7193-7207
Med.C...
CDK8 in oncology
marked modulation of selectivity profile within deep pocket - controversial
Steady increase in selectivit...
14
IC50(M)
similar potency;
huge difference in residence time
similar residence time;
difference in potency
Residence time...
15
compound synthesis in DNA-cavity
 Holliday Junction
50 Mio compound library
linear and branched compounds
spiked with ...
p38a as a prototypic kinase amenable to type II inhibition
Tri-peptide mimetics for kinases ?
16
IC50>2µM
% remaining acti...
Hydrophobic R-spine disrupted
17
Vpc00628
Hinge binding via single hydrogen bond – DFG out
Stephan Knapp, SGC Oxford, UK
Structurally Related Inhibitors
18
rapid interrogation of SAR by point mutations in compound structure
Advantage of modular chemistry
N
H
O
N
N
NH2
O
N
H
NH2...
summary
• pharmaceutically relevant targets cluster into densely
populated families
• high Fsp3 compounds pursuing an indi...
www.mercachem.com
Arjen Brussard
Tim Moser
Christoph Schächtele
Michael Kubbutat
Nils Jakob Vesten Hansen
Tara Heitner Han...
Upcoming SlideShare
Loading in …5
×

GMueller_Barcelona

715 views

Published on

  • Be the first to comment

  • Be the first to like this

GMueller_Barcelona

  1. 1. Target Family-Centric Privileged Structures: unexploited opportunities for medicinal chemistry Gerhard Müller Senior Vice President Medicinal Chemistry Mercachem bv gerhard.mueller@mercachem.com
  2. 2. • Bayer Pharma AG • AstraZeneca AB • H. Lundbeck A/S • Janssen Pharma NV • Merck KGaA • Sanofi • UCB Pharma SA 300.000 compound library to be complemented with 200.000 novel compounds 400 novel scaffolds  non-mainstream  structural complexity  stereochemistry  scaffold diversity  challenging chemistry €196 million pan-European drug discovery platform WP9: Program Recruitment (crowd-) sourcing of proposals from e.g. academia WP10: Review & Selection Library Selection Committee (Prof. Adam Nelson) WP11: Experimental Validation Validation Management Team (Mercachem) WP12: Library Generation 5 SMEs involved, each SME: 8000 compounds annually based on 16 scaffolds annually European Lead Factory – 200.000 novel „non-main stream“ compounds attempts to surf the chemical space 2 as of May 1st: 680 scaffolds reviewed > 390 scaffolds approved ~ 140 scaffolds validated ~50.000 compounds made
  3. 3. “What is clear is that certain “privileged structures“ are capable of providing useful ligands for more than one receptor …“ “… judicious modification of such structures could be a viable alternative in the search for new receptor agonists and antagonists” B. E. Evans et al. J. Med. Chem., 31, 2235 (1988) A. A. Patchett et al. Annu. Rep. Med. Chem. 35, 289 (2000) G. Müller, Drug Discovery Today 8, 681-691 (2003) one ligand for more than one target system – very generic – no teaching! navigating with privileged structures N N N H O S F tifluadom k-opioid agonist Nature, 298, 759 (1982) CCK-A antagonist Neurosci. Lett., 72, 211 (1982) 3 N H N O N OH N N O Merck: ORL1 antagonist Roche: ORL1 agonists N N H N O N N NH delete bond Dan Rich, 1990’s Prevent hydrophobic collapse
  4. 4. Spirocyclic compounds:  conformationally constrained  -TDS   frequently occur in natural products  protein binding   characteristic three-dimensionality  shape   structural novelty  IP   Fsp3-rich carbon skeleton  increasingly utilized in drug discovery  numerous therapeutical areas, often CNS  majority of spiro chem space unexplored! 1857 compounds active at 200 targets 75 GPCRs (!) quantitative analysis of molecular spiro topologies spiro systems 4 CGRP-1 V1a, V1b, V2 sstr1, sstr2, sstr3, sstr4, sstr5 A2a, A3 Nociceptin Oxytocin Orexin-1 µ-opioid, k-opioid, d-opioid s-opioid H3, H4 C5a GPCR-35 M1, M2, M3, M4, M5 Calcitonin-1 D1, D2, D3, D4, D5 a1a, a1b, a1d, a2a, a2b, a2d b1 adrenergic CB1, CB2 B1, B2 5-HT1a, 5-HT1b, 5-HT1d, 5-HT2a, 5-HT2b, 5-HT2c, 5-HT1a, 5-HT5a, 5-HT6, 5-HT7 MC1, MC3, MC4, MC5 mGluR5 MCHR-1, MCHR-2 Vanilloid Neuromedin B CGRP-1 NPY-2, NPY-5 CCR-1, CCR-2, CCR-3, CCR-5 NK1, NK2, NK3 Glucagon Melatonin-1B Prof. J. Bajorath
  5. 5. J. Mol. Biol., 425, 662-677 (2013) Convert GPCRs to soluble protein – biochemistry, biophysics, etc G7 Therapeutics 5 Long –term apo-state stability: No stabilizing ligand required – no pre-empted activation state Important for accessibility of fragments Unbiased on functional signature (ago, ant, inv.ago, etc) Detergent solubility: Isolated receptor protein in detergent micelles Vapor-diffusion crystallization works out Protein amenable to biochemistry and biophysics SPR, NMR, TINS, FBLG, kinetics, thermodynamics, etc. CHESS: Cellular High-Throughput Encapsulation Solubilising and Screening Class A GPCRs  Neurotensin 1 receptor (NTS1)  κ-opioid (KOR)  Tachykinin receptor 1 (NK1)  Oxytocin  Adrenergic receptors  α1A  α1B Class B GPCR  Parathyroid hormone receptor 1 (PTH1) Fig. S2. Quality of the σA-weighted 2FO-FCelectron density map contoured at 1.2 σ. Stere Directed evolution – error-prone PCR
  6. 6. O N O O Annelated ring systems – novelty analysis ongoing Fsp3-rich carbon skeletons annelation-constrained macrocycles • sp3-rich • stereochemical complexity • 3D shape • non-main stream 6 annelated 3796 compounds 395 BM scaffolds 401 unique targets [5:5] cyclopentan-pyrolidine [6:5] piperidino-pyrrolidine [5:5] pyrrolidino-diazolidine-dione g-exo-homo Proline [6:7] reverse turn mimic [6:5] reverse turn mimic
  7. 7. P. Furet et al. J. Comp.-Aid. Mol Des. 1995, 9, 465-472 P. Traxler, Exp.Opin. Ther. Patents 1998, 8, 1599-1625 N NN H N H O N N N stabilizing inactive kinase conformation NH N NH O O H O deep pocket Gleevec : c-Abl type II NH N NH O O H O back pocket N Cl Cl O N NN H S competitive inhibition of active state PD173955 : c-Abl 1m52.pdb PD173955 : c-Abl 1iep.pdb Gleevec : c-Abl DFG-in (I) vs. DFG-out (II) activation loop undergoes significant structural rearrangement type I DFG-in DFG-out 7
  8. 8. DFGin DFGout many „DFG-in-between“ ? misleading terminology A.P. Kornev, N. M. Haste, S. S. Taylor, L. F. Ten Eyck, Proc. Natl. Acad. Sci., 103, 17783 (2006) A.P. Kornev, S. S. Taylor, L. F. Ten Eyck, Proc. Natl. Acad. Sci., 105, 14377 (2008) A.P. Kornev, S. S. Taylor, Biochim. Biophys. Acta, 1804, 440-444 (2010) H.S. Meharena, et al, PLOS Biology, 11 (10), 1-11 (2013) 8
  9. 9. hydrophobic spine comparison of intact and disrupted spines O N N H O N H N H O Cl CF3 intact R-spine disrupted R-spine (CDK8) 9 active kinase type I inhibitors fast kinetics inactive kinase non-type I inhibitors slow kinetics (t½ 8 h)
  10. 10. Retro-Design Approach: B2F (back-to-front)  Sets out with scaffolds rather than leads  Disrupt hydrophobic spine  Long residence time on target; slow koff  Option for exploration of novel IP space  Option for increased selectivity NH N NH O O H O “Retro Design“ approach targeting conformational states by deep pocket-directed scaffolds 10
  11. 11. UPR as one major cause for neurodegeneration AD disease mechanisms: UPR ER UPR (unfolded protein response): • cellular stress pathway • protein misfolding in ER = stress • stress sensors: • PERK, ATF6, IRE1 • „sense“ mis-folded proteins • expression of Chaperons – assist in protein folding 11 pPERK Phospho-Tau (AT8) Hippocampus anatomy PERK
  12. 12. N N N NH2 N O N CH3 F GSK2656157 (IC50: 0.8 nM) development candidate WO2011119663A1 J.Med.Chem. 2012, 55, 7193-7207 Med.Chem.Lett. 2013, 4 (10), pp 964–968 IC50: 2.72 nM Novel, IP-free scaffold 12 4x7n4g313qd2 R-Sp2 and R-Sp3 inhibition mode = f(inhibitor) hydrophobic spine topology
  13. 13. CDK8 in oncology marked modulation of selectivity profile within deep pocket - controversial Steady increase in selectivity throughout the consecutive compound generations Initial generation Novel generation Latest generation 13 See poster 25
  14. 14. 14 IC50(M) similar potency; huge difference in residence time similar residence time; difference in potency Residence time (h) similar potency; huge difference in residence time Escape Trajectory: retrograde induced-fit mechanims of dissociation IC50 / koff Correlation (?) With appreciation to R. Buijsman, NTRC, Oss, NL Ponatinib d on off K k k  P + L PL ΔG‡ on ΔGd ΔG‡ off RT/G- on ‡ on ek D  RT/G- off ‡ off ek D  /RTG-Δ d eK d  Bindingcoordinate
  15. 15. 15 compound synthesis in DNA-cavity  Holliday Junction 50 Mio compound library linear and branched compounds spiked with PPI motifs • turns (beta and gamma) • strands (exteded conformations) • Trp, Arg, Tyr Protein-Protein Interaction-targeted Library DNA-encoded Library Technology
  16. 16. p38a as a prototypic kinase amenable to type II inhibition Tri-peptide mimetics for kinases ? 16 IC50>2µM % remaining activity @ 2µM compound concentration 0 25 50 75 100
  17. 17. Hydrophobic R-spine disrupted 17 Vpc00628 Hinge binding via single hydrogen bond – DFG out Stephan Knapp, SGC Oxford, UK
  18. 18. Structurally Related Inhibitors 18
  19. 19. rapid interrogation of SAR by point mutations in compound structure Advantage of modular chemistry N H O N N NH2 O N H NH2 O required ? R-groups heterocycles ring size acceptor ! ring size heterocycles R-groups required ? NH-Me, Cl, F Me, CF3 stabilize kinked cofo! stereochemistry small substituents spacing heterocycles R-groups ring size scan pocket better change physchem stabilize cofo donor required ! spacing, b-AA NH-R, explore pocket Weeks 1 2 3 4 5 6 step 1: amide coupling step 1: purification Step 2: Pg removal Step 2: purification Step 3: amide coupling Step 4: purification Unfold near-to-complete SAR in 6 weeks of chemistry Iterative analogue libraries 19
  20. 20. summary • pharmaceutically relevant targets cluster into densely populated families • high Fsp3 compounds pursuing an indirect approach chemical similarity correlates with biological similarity • target family-centric rationales allow for imprinting family-wide commonalities into new scaffolds • functional attributes can be pre-engineered you might want to look for slow-off compounds • despite the run on epigenetic targets, the days of kinases are not yet over • DNA-encoded library approaches uncover truly novel chemotypes for target families 20 consider binding kinetics optimize residence time for multiple reasons Bob Copeland (CSO Epizyme Inc.) 10th Swiss med chem course, Leysin, 2012 „any chemist reporting IC50‘s should be boiled in oil!“
  21. 21. www.mercachem.com Arjen Brussard Tim Moser Christoph Schächtele Michael Kubbutat Nils Jakob Vesten Hansen Tara Heitner Hansen Kiyoshi Takayama Tomoko Shimizu Jürgen Bajorath Dagmar Stumpfe Carlo Bertozzi Lutz Kummer

×