2. Academic Validation
  3. Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165

Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165

  • J Med Chem. 2019 Oct 24;62(20):8973-8995. doi: 10.1021/acs.jmedchem.9b00444.
Stephen T Wrobleski,  Ryan Moslin,  Shuqun Lin,  Yanlei Zhang,  Steven Spergel,  James Kempson,  John S Tokarski,  Joann Strnad,  Adriana Zupa-Fernandez,  Lihong Cheng,  David Shuster,  Kathleen Gillooly,  Xiaoxia Yang,  Elizabeth Heimrich,  Kim W McIntyre,  Charu Chaudhry,  Javed Khan,  Max Ruzanov,  Jeffrey Tredup,  Dawn Mulligan,  Dianlin Xie,  Huadong Sun,  Christine Huang,  Celia D'Arienzo,  Nelly Aranibar,  Manoj Chiney,  Anjaneya Chimalakonda,  William J Pitts,  Louis Lombardo,  Percy H Carter,  James R Burke,  David S Weinstein
PMID: 31318208 DOI: 10.1021/acs.jmedchem.9b00444
Abstract

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for Tyk2 relies on targeting the Tyk2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of Tyk2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.

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