2. Academic Validation
  3. Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2

Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2

  • J Med Chem. 2021 Jan 14;64(1):677-694. doi: 10.1021/acs.jmedchem.0c01698.
Chunjian Liu 1,  James Lin 1,  Charles Langevine 1,  Daniel Smith 2,  Jianqing Li 2,  John S Tokarski 3,  Javed Khan 3,  Max Ruzanov 3,  Joann Strnad 4,  Adriana Zupa-Fernandez 4,  Lihong Cheng 4,  Kathleen M Gillooly 4,  David Shuster 4,  Yifan Zhang 4,  Anil Thankappan 4,  Kim W McIntyre 4,  Charu Chaudhry 5,  Paul A Elzinga 6,  Manoj Chiney 6,  Anjaneya Chimalakonda 6,  Louis J Lombardo 1,  John E Macor 1,  Percy H Carter 1,  James R Burke 4,  David S Weinstein 1
Affiliations

Affiliations

  • 1 Immunosciences Discovery Chemistry, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • 2 Department of Discovery Synthesis, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • 3 Molecular Structure and Design, Molecular Discovery Technologies, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • 4 Immunosciences Discovery Biology, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • 5 Leads Discovery and Optimization, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
  • 6 Metabolism and Pharmacokinetic Department, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
PMID: 33370104 DOI: 10.1021/acs.jmedchem.0c01698
Abstract

A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 Inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 Inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.

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