Discovery and Development of Highly Selective and Orally Bioavailable Macrocyclic IDO-1 Inhibitors

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1 Discovery and Development of Highly Selective and Orally Bioavailable Macrocyclic IDO-1 Inhibitors 1 Tim Briggs Senior Director, Medicinal Chemistry Ensemble Therapeutics Corp. Ensemble Therapeutics Corp

2 2 Rapidly developing IDO1 program Inhibitors show great promise in cancer therapy Hottest immunotherapy pathway successfully targeted with small molecules Incyte s Epacadostat in Phase 2 clinical trials as a First-In-Class IDO1 orally delivered small molecule Major alliances and acquisitions between biotech in big pharma: Genentech/New Link Genetics BMS/Flexus Pfizer/iTeos Merck/Iomet 2

3 Ensemble Therapeutics Trailblazers in Drug Discovery Founded in 2004 by Harvard Professor David Liu to develop DNAencoded libraries of macrocycles Amassed a multi-million membered library of macrocycles Evolved into more than a Discovery company Work with corporate partners and internally in developing small molecule therapeutics 3

4 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 Remarkable affinity and specificity 4 GPCRs/ Aminergic Receptors Small Simple Structure MW TOX issues from long half-lives Futile against intracellular targets Large Complex Structure 10,000 to 500,000 MW 4

5 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 5 Kinases GPCRs/ Aminergic Receptors Small Simple Structure MW Medium-sized molecules with drug-like properties Large Complex Structure 10,000 to 500,000 MW 5

6 Ensemble focuses on macrocycles Large proportion of non-lipinski oral drugs are macrocycles 38% of >500 MW drugs are macrocycles 2014, 57 (2), pp Propensity to be higher MW with druglike properties Macrocycles provide good starting points in developing oral non- Lipinski small molecule drugs 6 Cyclosporin (Novartis) Immunosuppressant 5-60% Oral BAV MW 1200 Josamycin (Bayer) Antibiotic 95% Oral BAV MW 828 Simeprevir (Janssen) Hepatitis 25-72% Oral BAV MW 750

7 7 Ensemble Drug Development More than a discovery platform Pharmacokinetics Drug distribution Pharmacodynamics Work internally and closely with corporate partners in drug development First-in-class small molecule inhibitors of IL17A licensed to Novartis Expertise in drugging small molecules in non-lipinski chemical space 7

8 9 Ensemble s Product Pipeline 8

9 Why the interest in IDO? Not a typical Ensemble target Highly competitive field, late to the party Field dominated by small molecules that bind to the heme or in nearby binding regions No reported inhibitors that bind outside this region Crystal structures reveal two compact binding pockets near heme active site Targeting allosteric binding sites with ETx macrocycles Epacadostat GDC-0919 analogue 9 Need to be unique Need to be fast Need to be best 9

10 Ensemble Drug Discovery Engine Lead discovery Efficient platform can produce lead series within 2 months 10

11 Rapid discovery of lead series against IDO Verification of potent hit in 2 months Encoded Libraries IDO-Based Affinity Screening + ETx-8489 Cell IC µm Multiple unique series identified with affinity to IDO Series identified by DNA codon KTFBB advanced with <1 µm cell activity 11

12 Rapid development of highly permeable and potent IDO inhibitors Lead from initial screen ETx-8489 Candidate for PD study ETx-9132 Hela Cell Activity, IC 50 [µm] Caco-2 Cell Perm. (AB), [P app x 10-6 cm/s] < Rat Oral BAV [%F] Mouse Oral BAV [%F] ETx-9132 dosed 100 mg/kg PO in mice Developed lead from screen into candidate for Proof of Concept PD study in two months ETx-9132 activity in Hela cells 12

13 Thermal shift correlates with cell activity Thermal stability assay IDO1 ETx-8951 ETx-9133 Compound Cell IC50 (µm) Change in T M ( C) ETx-0406 >10 0 ETx ETx ETx ETx ETx ETx Protein is stabilized to denaturation in presence of ETx IDO inhibitors Dramatic shift in melting temperature (T M ) of IDO from 44 to >60 C 13

14 Evidence of allosteric binding mode Inhibitors do not bind to heme Evaluation of Heme-Binding X = IDO1 = IDO1 + ETx-8952 = IDO1 + ETx-8951 X = IDO1 + Phenyl triazole = IDO1 + INCB inhibitor = Buffer Rohrig et al, JMC, 2012, Heme incorporated IDO exhibits a Soret peak at 404 nm Known IDO heme binders show considerable shift in Soret peak ETx IDO inhibitors do not shift peak, do not bind to the heme 14

15 ETx inhibitors highly specific to IDO >100K more selective verse TDO TDO (tryptophan 2,3-dioxygenase) belongs in same family of enzymes as IDO Function is analogous to IDO in the metabolism of tryptophan Share structural similarity in heme containing active site, but show low homology (<10%) ETx-9132 is >13,000-fold more selective for IDO than GDC-919 Compound hido IC 50 (mm) htdo IC 50 (mm) Fold- Selective ETx ,000 GDC * 0.140* 11 Epacadostat 0.020** 5** 350 * As reported at AACR April, 2014, poster 1633 ** Assayed at ETx ETx-9132 clean in CEREP panel of 30 additional targets at 10 µm 15

16 Cell assay study demonstrates IDO specificity Inhibition determined by monitoring oxidation of tryptophan to N- formylkynurenine SW48 colon cancer have high TDO expression (no significant levels of IDO) IDO can be expressed in SW48 or Hela cells by INF ETx-9132 inhibits IDO pathway, no effect at slowing Trp oxidation in cells deficient in IDO Trp oxidation by IDO Trp oxidation by IDO and TDO Trp oxidation by TDO 16 [ETx-9132], µm

17 Tumor Volume (mm 3 ) Pan02 Syngeneic Mouse Model Outstanding suppression of tumor growth 400 Tumor Volume vs. Time 300 Vehicle 200 ETx-9132, 100 mg/kg, PO BID 100 Dramatic suppression of Pan02 tumor growth Outstanding efficacy for an IDO1 inhibitor as a monotherapy Compound well tolerated at 100 mg/kg, BID No significant weight difference between compound and vehicle mice Study Days Histopath on organs show no sign of toxicity

18 Progression of ETx-9132 High oral exposure of advanced candidate ETx-9132 ETx-9668 Hela Cell Activity, IC 50 [µm] Solubility, µm Caco-2 Cell Perm. (AB), [P app x 10-6 cm/s] Rat Oral BAV at 100 mg/kg [%F] 13 >100 Rat IV Clearance (mg/ml/kg) Outstanding oral absorption achieved at high doses Highly soluble while maintaining good permeability Major liability to overcome towards Best-In-Class is improving rapid clearance in vivo 18

19 Discovery of ETx-0280 Primed for development candidate nomination ETx-9132 ETx-0280 ETx-0280 Hela Cell Activity, IC 50 [µm] Rat Oral BAV,10 mg/kg [%F] 50 Rat IV Clearance, 1 mg/kg (mg/ml/kg) 9 Optimization of PK properties lead to discovery ETx-0280 >15 fold higher oral exposure in mouse at 100 mg/kg (PD dose) High oral BAV and low clearance at low dose in vivo in rat Nomination of development candidate targeted early Q3 19

20 20 Towards a Best-In-Class IDO inhibitor Unique First reported allosteric inhibitor of IDO Fast Screening to development candidate nomination in 1 year Best Unprecedented cell potency achieved Outstanding tumor suppression for IDO monotherapy in early compound Exceptional PK in advanced highly potent IDO inhibitors 20 Ensemble drug discovery engine powerful in ability to rapidly discover and develop nontraditional small molecule therapeutics

21 Scientific acknowledgements Libraries David Boulay Bill Connors Shukui Guan Daniel Wang Biology and Informatics Steve Hale, CSO Sethu Alexander Julian Bond Yan Chang Deborah Dodge Rich Martinelli Revonda Mehovic Medicinal Chemistry Tyler Cipriani Heather Davis Jeremy Duvall Frank Favaloro Jun Jiang Lizzie Jones Maurice Lee Giovanni Muncipinto Chris Oalmann Kelley Shortsleeves Cheri Snedeker Dingxue Yan 21 Ensemble Therapeutics Corp