Discovery and Development of Oral Therapeutics Against Challenging Protein Targets

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1 Discovery and Development of Oral Therapeutics Against Challenging Protein Targets Tim Briggs Senior Director, Medicinal Chemistry Ensemble Therapeutics Corp. Ensemble Therapeutics Corp

2 2 Trailblazers in drug discovery Ensemble s drug discovery engine discovers and develops drug-like compounds against difficult-to-drug targets corporate partnerships internal programs IMMUNO-ONCOLOGY check point inhibitors

3 3 Trailblazers in drug discovery Ensemble s drug discovery engine discovers and develops drug-like compounds against difficult-to-drug targets corporate partnerships Development of small molecule IL17A antagonists internal programs Rapid discovery and development of macrocycles that inhibit IDO1

4 4 Targeting Protein-Protein Interfaces Challenging targets for small molecules 20 years ago considered undruggable by small molecules Sequencing of human genome uncovers more PPI targets larger binding interface than traditional enzyme targets Big pharma has been unsuccessful targeting with small molecules Huge opportunity and need for small molecules oral therapeutics targeting PPIs

5 Why have small molecules been unsuccessful against PPIs? Not addressed by traditional small molecules 5 Larger binding sites require larger molecules to bind Larger molecules are more difficult to drug Necessary to go beyond the Rule of Five when targeting PPIS Screening libraries have bias towards Rule of Five compliancy Guidelines imposed in big pharma impede development

6 Going Beyond the Rule of Five Reassessing chemical properties required for oral bioavailability Kihlberg et al. Chemistry and Biology, 2014, Survey of >500 MW drugs or candidates Lipinkski Ro5 (1997) likely to be oral MW 500 Da 0 clogp 5 HBD 5 HBA 10 PSA 140 Å 2 NRotB 10 Kihlberg bro5 (2014) possibility to be oral MW 1000 Da -2 clogp 10 HBD 6 HBA 15 PSA 250 Å 2 NRotB orally administered Lends insight into properties dictating oral bioavailability Beyond Rule of Five molecules can be drugged; need more insight to better predict oral bioavailability 6

7 7 Ensemble focuses on macrocycles Large proportion of bro5 oral drugs are macrocycles 2014, 57 (2), pp Cyclosporin (Novartis) Immunosuppressant 5-60% Oral BAV MW macrocycle drugs/candidates - 2% of all oral drugs - 38% of >500 MW drugs Josamycin (Yamanouchi/Bayer) Antibiotic 95% Oral BAV MW 828 Macrocycles provide good starting points in developing oral non- Lipinski small molecule drugs Simeprevir (Janssen) Hepatitis 25-72% Oral BAV MW750

8 Compact Binding Extended Binding Antibodies successful against PPIs Not amenable to oral delivery Target types ANTIBODIES Protein- Protein Interactions Proteases, phosphatases SMALL MOLECULE DRUGS Kinases GPCRs/ Aminergic Receptors Small Simple Structure MW Remarkable affinity and specificity TOX issues from long half-lives Futile against intracellular targets Large Complex Structure 10,000 to 500,000 MW 8

9 Compact Binding Extended Binding Ensemble creates macrocycle libraries Hitting the targets of biologicals with drug-like molecules Target types ANTIBODIES Protein- Protein Interactions Proteases, phosphatases MACROCYCLES Kinases GPCRs/ Aminergic Receptors Small Simple Structure MW Medium-sized molecules with drug-like properties Large Complex Structure 10,000 to 500,000 MW 9

10 10 Ensemble Drug Discovery Engine Lead discovery DPC library synthesis Affinity-based selection assays Sequencing and Informatics Hit ID Comprehensive SAR DNA-Programmed Chemical Synthesis Lead determination Large Diverse Macrocycle Libraries Hit validation Compound synthesis Lead series Biochemical, biophysical, and cell assays Efficient platform can produce lead series within 2 months

11 11 Ensemble Drug Development More than a discovery platform Ensemble not solely a discovery company Pharmacokinetics Work internally and closely with corporate partners in drug development Drug distribution Expertise in drugging small molecules in non-lipinski chemical space Pharmacodynamics

12 12 Evolution of Ensemble Discovery Therapeutics Utilize DNA-programmed chemistry to create screenable DNA-encoded libraries of macrocycles - >15 million macrocycles; >50 targets Verify hits from screens translate to binders off DNA - IL17A, xiap, MDM2, CypA, CypD, USP9, IDO1, multiple undisclosed partner targets Discovery leads into development candidates - xiap program partnered with BMS - IL17A antagonists partnered with Novartis - Internal program against IDO1

13 Development of small molecule IL17 antagonists Clinically validated target in psoriasis 13 Implicated in inflammatory and autoimmune disease IL17A:IL17A-Receptor Complex Tertiary binding epitope (2200 Å 2 ) No published reports of small molecule inhibitors Oral therapeutic would expand treatment class

14 14 Hit from Ensemble library developed into highly potent macrocycle lead Breakthrough in targeting PPIs Ensemble macrocycle libraries generated hits K D 1 µm MedChem verifies hits off DNA Iterative MedChem campaign Potent macrocycle lead K D µm Cell µm Recently, Ensemble Therapeutics disclosed the development of a macrocyclic compound that inhibits binding of interleukin-17 (IL-17) to its receptor which represents a breakthrough. We eagerly await publication of the structural and preclinical data surrounding this program. - Arkin, Wells et al, Chemistry and Biology 2014, 21, 1104.

15 Similar binding to IL17A antibodies at fraction of the size Macrocycle <1% of molecular weight of antibody Antibody IL17A inhibitor (MW 150K Da) Macrocycle IL17A inhibitor ( 800 Da) K D = 200 pm off rate = 400 min K D = 100 pm off rate = 300 min Currently being developed with Novartis towards an oral therapeutic 15

16 16 Ensemble immuno-oncology program Pursuing inhibitors of immune checkpoint targets Controlling the immune system to fight cancer Many checkpoint targets are PPIs (e.g. PD1, CTLA4) Small molecule alternative to current antibody therapeutics - Safety - Cell/tumor penetration - Oral administration - Intellectual property

17 17 Rapidly developing IDO1 program Inhibitors show great promise in cancer therapy Overexpressed in many cancers - permits tumor cells to escape immune system Combination therapies with inhibitors of other checkpoint targets show great promise Macrocycles bring unique approach to competitive field - Potential for greater target specificity

18 18 Rapid discovery of lead series Low nanomolar activity in 5 months N H O H N O O O OH NH HN H N O E IC nm E IC50 15 nm N H NH O UHT Screening of DNAencoded macrocycle libraries against IDO1 3/2015 Sequencing and Informatics ID hits 4/2015 Discrete compound synthesized and screened for biochemical analysis 5/2015 Initial MedChem 7/2015 Ensemble discovery engine rapidly discovers lead (2-3 months) MedChem verifies hit and lowers potency (2 months)

19 19 Library hit provides good starting point Compliant to Kihlberg s bro5 original hit Lipinski Ro5 Kihlberg bro5 E Enzymatic assay, IC 50 [µm] 0.10 Cell %inhibition, 10 µm 0% MW 500 Da 1000 Da 950 clogp HBD HBA PSA 140 Å Å Although no cell activity properties suggest within reach

20 20 Altering chemical properties results in cell activity Lipinski Ro5 Kihlberg bro5 original hit E E Enzymatic assay, IC 50 [µm] Cell %inhibition, 10 µm 0% 60% MW 500 Da 1000 Da clogp HBD HBA PSA 140 Å Å Modifications to improve permeability result in cell activity!

21 21 Ensemble checkpoint program status On path towards specific oral IDO1 inhibitor In 5 months have demonstrated low nanomolar enzymatic activity and cell activity against IDO1 Target specificity - Specific to human IDO1 over human TDO and murine IDO1 Pursuing small molecules against other checkpoint targets - TDO, CTLA4, PD1, PDL2

22 22 Ensemble Therapeutics Trailblazers in drug discovery Huge growing market and need for oral therapeutics targeting protein-protein interactions (PPIs) Dual challenge of finding chemical matter and transforming into an oral therapeutic Ensemble s discovery platform successful in producing leads Ensemble s drug development team posed to deliver nontraditional small molecule oral therapeutics

23 23 Ensemble Therapeutics Trailblazers in drug discovery Necessary to push boundaries and remove bias from traditional small molecule drug development Know the rules well, so you can break them effectively -Dalai Lama

24 Scientific acknowledgements Libraries David Boulay Bill Connors Shukui Guan Daniel Wang Screening/Biology Sethu Alexander Julian Bond Yan Chang Deborah Dodge Stephen Hale Sarah Jensen Rich Martinelli Revonda Mehovic Nathan Walsh Medicinal Chemistry Tyler Cipriani Jeremy Duvall Frank Favaloro Jun Jiang Lizzie Jones Maurice Lee Giovanni Muncipinto Chris Oalmann Kelley Shortsleeves Cheri Snedeker Nick Terrett Dingxue Yan Ensemble Therapeutics Corp