Medicinal chemistry Capabilities

1. Presentation for The
Structure Based Drug
Design Conference
Cambridge. MA 2009

2. Track Record
Domainex’s contribution to client drug discovery
programmes has directly resulted in
three clinical candidates.
Ion-channel blockers
• Based upon several Leadbuilder-derived active series, optimisation led
to selective compounds, culminating in the identification of a clinical
candidate.
Kinase Inhibitors
• A close analogue of a compound we made for a client is now in clinical
trials.
Anti-thrombotics
• We designed and synthesised a series of novel anti-thrombotics, and a
compound from this programme is being evaluated in clinical trials.

3. People
• 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.

4. Technologies
• 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,
screening sets.
• Integrated Medicinal and Computational
Chemistry : for rapid progression of hits to
deliver candidate drugs.

5. Example 1: An ion-channel blocker currently in
clinical development
• Hit Identification:
– We prepared a comprehensive database
of ~1000 diverse sodium and potassium
channel blockers reported in the
literature.
– Analysed this database to derive
pharmacophores and counter-
pharmacophores.
– LeadBuilder was used to select a focussed
screening deck.
– 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
clinical development
• Hit-to-lead investigation of three distinct chemical
classes to improve:
– Potency.
– 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
clinical development
• Lead compound had electrophys. IC50
60nM and an acceptable
physicochemical and PK profile.
– But no selectivity vs closely related
ion-channels.
• 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.
• Resource:
– 3.5 FTE x 15 months.

8. Example 2: Kinase Lead Optimisation
• Our client requested a series of focused libraries directed at a
kinase target.
• 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
mg/compound.
• 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.
"Warhead"
O P2
"Cap" H H Lead identification:
N N
N • A series of reversible “warheads”
H
P3 O P1 capable of interacting with the catalytic
residues of the protease were
investigated.
Molecular modeling • 1st generation reversible inhibitors:
Synthesis IC50 in range 1-10 µM.
Screening •Resource: 2 FTE x 6 months
Lead Identification

11. Example 3: Protease inhibitors
Lead Optimisation:
• 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
medicinal chemistry.
• 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
ligand.
• 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
Crystallographically observed
Four‐point pharmacophore
binding of autoinhibitory loop (red)

15. Example 5: Hit ID for a kinase target
• We selected 436 high-priority compounds for
screening.
• 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.
• Follow-up:
– Compounds are patentable.
– Our Client is securing funding based upon this IP.
– We are designing a hit-to-lead programme around these
series.

16. Further examples of our success in drug
discovery…
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
programmes.
• We have generated compounds active in enzyme and cellular assays,
leading to novel patent filings.
Metabolic Diseases
• 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
success?

18. Medicinal Chemistry
• A team of highly-experienced
medicinal chemists:
– with an industrial pedigree.
– a strong track record of successful drug
discovery.
• 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-
infectives, etc.

19. Medicinal Chemistry
Design Synthesis
• 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.

20. LeadBuilder
• A cost-effective route to high-quality drug
leads:
– 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.

21. LeadBuilder
LibraryBuilder
•Virtual Compound Collection
•CompoundProfiler
StructureBuilder
ScreenBuilder
•X-ray structure
•Virtual screening
•Homology modelling
Screening Platform
Biochemical NMR
Screening Screening

22. LibraryBuilder filters
Log P Hit-like starting points
5.0
Optimised Elimination of
within 300 weak binders
Drug-like
drug-space
3.5 using
Hit-like calculated
200
Hit compound: binding
2.5 MW 325
Log P 3.0 energies
100
250 350 500 MW 5kcal/mol
300 Elimination of
Predicted known
Solubility toxophores,
200
>10µM predicted good
absorption
100
-4 -3 -2 -1 0

23. Synthetic Chemistry
• We have a team of talented PhD qualified synthetic
chemists:
– Many years of industrial experience.
– An exceptional track record of success with demanding
chemistries.
• 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
parallel synthesis.
– 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.
– Docking.
• Small-molecule modelling:
– Pharmacophore analysis.
– Conformational analysis.
– Scaffold-morphing.
• Cheminformatics:
– Target assessment: “drugability”, specificity, etc.
– LeadBuilder: selection of compounds for screening.
– Molecular and physicochemical property profiling.
– ADME-tox prediction.

26. PharmaProfiler
• A highly representative selection of commercial small-
molecule drugs:
– 320 compounds = 30% of pharmacopeia.
• Designed for optimal coverage of drug classes and
therapeutic indications.
• Ready formatted: pre-solubilised in assay-ready 96-
well plates.
• Useful in a variety of screening situations, including:
– lead-finding.
– assay validation.
– repurposing of known drugs onto novel targets.

27. PharmaProfiler drug classification
GPCR 74
Ion Channel 33
Nuclear
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
Parenteral 80
Other Enzyme 67 Analgesic 22
Other 56 Topical 19
Other 58
Table 1: Table 2: PharmaProfiler Table 3: PharmaProfiler
PharmaProfiler drugs drugs classified by drugs classified by
classified by Target Therapeutic Area Route of Administration
Class

28. Conclusions
• 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
experienced scientists.
• We focus upon efficient communication with
clients - in most cases we are fully integrated
into their project teams.