1. Presentation for The
Structure Based Drug
Cambridge. MA 2009
2. Track Record
Domainex’s contribution to client drug discovery
programmes has directly resulted in
three clinical candidates.
• Based upon several Leadbuilder-derived active series, optimisation led
to selective compounds, culminating in the identification of a clinical
• A close analogue of a compound we made for a client is now in clinical
• We designed and synthesised a series of novel anti-thrombotics, and a
compound from this programme is being evaluated in clinical trials.
• Highly experienced team of drug hunters
• >90% with PhDs.
• Average age 35.
• Most have significant prior experience in other
companies including: Astex, AstraZeneca,
BioFocus, Celltech, DeNovo, Evotec, GSK,
Medivir, Millennium, Rhone-Poulenc, UCB.
• Combinatorial Domain Hunting (CDH) :
allows us to identify soluble protein constructs
for screening and structural biology.
• LeadBuilder : state-of-the-art capability in
virtual screening to select small, focussed,
• Integrated Medicinal and Computational
Chemistry : for rapid progression of hits to
deliver candidate drugs.
5. Example 1: An ion-channel blocker currently in
• Hit Identification:
– We prepared a comprehensive database
of ~1000 diverse sodium and potassium
channel blockers reported in the
– Analysed this database to derive
pharmacophores and counter-
– LeadBuilder was used to select a focussed
– Screening of this deck gave several µM and sub-
µM hits, for example:
• IC50 = 0.32µM, MW 307, PSA 51Å2, LogP <4.
6. Example 1: An ion-channel blocker currently in
• Hit-to-lead investigation of three distinct chemical
classes to improve:
– Solubility and microsomal stability.
– IP position: novel biological activity, but requirement to design
away from unrelated patents.
Domainex Competitor A Competitor B Competitor C
%inhibition @1µM 97 99 99 95
Solubility µM 194 12 0 34
% Remaining HLM 84 1 ND 1
• Resource: 3 FTE x 3 months
7. Example 1: An ion-channel blocker currently in
• Lead compound had electrophys. IC50
60nM and an acceptable
physicochemical and PK profile.
– But no selectivity vs closely related
• Comparative 3D models of the target
channel and non-targets were built.
• Lead optimisation led to selective compounds, culminating in the
identification of a Clinical Candidate.
– Currently in Phase 1 Trials.
– 3.5 FTE x 15 months.
8. Example 2: Kinase Lead Optimisation
• Our client requested a series of focused libraries directed at a
• Domainex designed these libraries:
– To explore novel chemical space around the lead scaffold.
– Using CompoundProfiler to ensure “drug-like” properties
• Predicted physicochemical and ADMET profiles
• Using a combination of proprietary and in-house algorithms
• Based upon the Accelrys Pipeline Pilot platform
• Library chemistries were devised and optimised by Domainex chemists.
9. Example 2: Kinase Lead Optimisation
• Library construction:
– Domainex developed routes to the key common intermediates.
• Synthesised either in-house or sub-contracted.
– Prepared the libraries using parallel synthesis methods.
– Compounds prepared to >95% purity using preparative LC-MS.
– A total of approx. 500 compounds delivered @ >10
• Results of Biological testing:
– Screening of the libraries revealed a number of active areas.
– A very close analogue of one of the library members designed
and made by Domainex is currently in clinical trials.
10. Example 3: Protease inhibitors
• The Client’s target was a protease believed to be relevant to the
treatment of asthma.
• Our starting point was a series of peptidic irreversible inhibitors:
– Potent, but deemed unsuitable for further development.
• We were required to prepare reversible inhibitors that would be
suitable for an inhaled therapy.
"Cap" H H Lead identification:
N • A series of reversible “warheads”
P3 O P1 capable of interacting with the catalytic
residues of the protease were
Molecular modeling • 1st generation reversible inhibitors:
Synthesis IC50 in range 1-10 µM.
Screening •Resource: 2 FTE x 6 months
11. Example 3: Protease inhibitors
• From these leads Domainex has developed potent reversible inhibitors.
– Improving interactions with the specificity pockets of the protease.
– Reduce proteolytic degradation by incorporating unnatural amino
acids and/or appropriate amide isosteres at key positions.
• Structure-based drug design has played a key role in guiding the
• Current lead compounds:
– IC50 < 10 nM.
– Good solubility, and stable in the presence
of various rat and human lung cells.
– Active in animal POC studies.
• Resource : 2 FTEs x 9 months.
12. Example 4: “Patent busting”
• Our client wanted us to rapidly generate a patentable
compound based upon a competitor’s IP.
• We undertook a careful analysis of the SAR revealed
in their application and the patent claims.
• We made a handful of compounds that were novel but
with a minimal number of changes from the prior art.
• One of these compounds was similar in potency to the
competitor product, but with an improved PK profile
and has been taken into Development.
13. Example 5: Hit ID for a kinase target
• Our Client postulated a novel allosteric
autoregulatory site – no known small molecule
• There was an x-ray structure of the protein
available to us.
• We used LeadBuilder to identify small
molecules that might bind to the target site.
1. Four-point pharmacophore screen.
2. Docking into binding pocket.
14. Example 5: Hit ID for a kinase target
binding of autoinhibitory loop (red)
15. Example 5: Hit ID for a kinase target
• We selected 436 high-priority compounds for
• Our Client tested these against the target @2µM:
– Gave 27 hits (6% hit rate).
– From four structural classes.
• 4 compounds showed good efficacy in a follow-up cell-
based screen @ 1 µM.
– Compounds are patentable.
– Our Client is securing funding based upon this IP.
– We are designing a hit-to-lead programme around these
16. Further examples of our success in drug
Cytotoxic Anti-cancer Agents
• Our client licensed IP for novel chemistry from a university.
• We Identified a subset of these compounds that had potential for
optimisation as cancer therapeutics.
• Our medicinal chemistry programme has already provided leads with
cellular activity 5-10x the commercial standards.
Enzyme Inhibitors (e.g. Kinases, Proteases)
• We have carried out many client programmes, including LeadBuilder for hit
finding; lead optimisation using structure-based design; and fast-follower
• We have generated compounds active in enzyme and cellular assays,
leading to novel patent filings.
• Based upon published literature and patents, we designed and synthesised
a series of novel enzyme inhibitors with pharmacokinetic and toxicity
advantages over competitors’ compounds.
• A compounds from this programme is currently in pre-clinical development.
17. How do we achieve this
18. Medicinal Chemistry
• A team of highly-experienced
– with an industrial pedigree.
– a strong track record of successful drug
• Great breadth of expertise:
– Target classes, including:
• Many enzyme classes, including kinases, proteases, etc.
• Cell surface receptors, such as GPCRs, cytokine receptors,
growth factor receptors, integrins, etc.
• Ion channels.
– Therapeutic areas, including:
• Cardiovascular, CNS, oncology, inflammation, respiratory, anti-
19. Medicinal Chemistry
• Drives synthesis. • Rapid, fit for purpose.
• Integrated design by • Parallel synthesis and
medicinal and microwave chemistry.
computational • Automated LCMS
chemists. Success - purification.
• Holistic design Quality and • High-quality analytical
(potency, ADMET, IP, speed support (NMR, LCMS,
etc). of each cycle etc).
• “Real time” SAR.
• Experimental design.
• Can be provided by DMX if a
spectrophotometric biochemical method.
• Otherwise provided by Client or by
Assay another CRO.
• DMX can also run kinetic solubility and
Cyp450 inhibition assays.
• A cost-effective route to high-quality drug
– Significantly enhanced hit rates in compound screening.
– High-quality hits – amendable to rapid progression.
– Time and cost saving by comparison with HTS.
– “Information-rich” hit-to-lead programmes.
• Virtual screening of curated databases of
commercially available compounds,
commercial drugs, etc:
– Selected to be “ideal” hit structures.
– Good ADMET and physicochemical profiles.
– “Biophillic” to enhance hit rates.
22. LibraryBuilder filters
Log P Hit-like starting points
Optimised Elimination of
within 300 weak binders
Hit compound: binding
2.5 MW 325
Log P 3.0 energies
250 350 500 MW 5kcal/mol
300 Elimination of
>10µM predicted good
-4 -3 -2 -1 0
23. Synthetic Chemistry
• We have a team of talented PhD qualified synthetic
– Many years of industrial experience.
– An exceptional track record of success with demanding
• Expertise in:
– Traditional synthesis.
– Parallel synthesis of chemical libraries.
– Microwave chemistry.
– Solid phase and peptide synthesis.
– Carbohydrate chemistry.
• Proven capabilities:
– Route scouting.
– Library and intermediate synthesis.
– Scale-up to 10’s of grams of final compound.
24. Chemistry Facilities
High quality laboratories:
– Fully equipped with traditional equipment
for organic synthesis.
– Microwave reactor with sample handler.
– Radleys Carousel and Greenhouse for
– Automated preparative LC-MS.
• Evaporation by Genevac and freeze-drying.
– Analytical LC-MS and HPLC.
– Local same-day access to comprehensive
analytical support (i.e. 1H & multi-nuclear
NMR, IR, UV, etc).
25. Computational Chemistry
• Protein modelling:
– Homology modelling.
• Small-molecule modelling:
– Pharmacophore analysis.
– Conformational analysis.
– Target assessment: “drugability”, specificity, etc.
– LeadBuilder: selection of compounds for screening.
– Molecular and physicochemical property profiling.
– ADME-tox prediction.
• A highly representative selection of commercial small-
– 320 compounds = 30% of pharmacopeia.
• Designed for optimal coverage of drug classes and
• Ready formatted: pre-solubilised in assay-ready 96-
• Useful in a variety of screening situations, including:
– assay validation.
– repurposing of known drugs onto novel targets.
27. PharmaProfiler drug classification
Ion Channel 33
Receptor 25 CNS 58
PDE 14 Oncology 40
Protease 13 Immune system 47
Kinase 12 Anti-infective 75
Transporter 16 Cardiovascular 58 Oral 267
Cytotoxic 22 Gastrointestinal 15
Other Enzyme 67 Analgesic 22
Other 56 Topical 19
Table 1: Table 2: PharmaProfiler Table 3: PharmaProfiler
PharmaProfiler drugs drugs classified by drugs classified by
classified by Target Therapeutic Area Route of Administration
• Domainex offers a range of technologies that
can be tailored to deliver a package to meet
specific client needs.
• High-quality drug hunting delivered by very
• We focus upon efficient communication with
clients - in most cases we are fully integrated
into their project teams.