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. Epub 2020 Dec 28.


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.

MeSH terms

  • Animals
  • Catalysis
  • Crystallography, X-Ray
  • Cyclopropanes / chemistry
  • Cyclopropanes / pharmacology*
  • Drug Discovery*
  • Humans
  • Mice
  • Oxazoles / chemistry
  • Oxazoles / pharmacology*
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Psoriasis / drug therapy
  • Structure-Activity Relationship
  • TYK2 Kinase / antagonists & inhibitors*
  • TYK2 Kinase / metabolism


  • BMS-986202
  • Cyclopropanes
  • Oxazoles
  • Protein Kinase Inhibitors
  • TYK2 Kinase
  • TYK2 protein, human