Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase

  • J Med Chem. 2022 Nov 10;65(21):14326-14336. doi: 10.1021/acs.jmedchem.2c01026.
Mark S Tichenor  1 ,  John J M Wiener  1 ,  Navin L Rao  2 ,  Genesis M Bacani  1 ,  Jianmei Wei  1 ,  Charlotte Pooley Deckhut  1 ,  J Kent Barbay  2 ,  Kevin D Kreutter  2 ,  Leon Chang  1 ,  Kathleen W Clancy  2 ,  Heather E Murrey  2 ,  Weixue Wang  2 ,  Kay Ahn  2 ,  Michael Huber  1 ,  Elizabeth Rex  1 ,  Kevin J Coe  1 ,  Jiejun Wu  1 ,  Haopeng Rui  3 ,  Kia Sepassi  1 ,  Marcello Gaudiano  4 ,  Mariette Bekkers  4 ,  Ivo Cornelissen  4 ,  Kathryn Packman  4 ,  Mark Seierstad  1 ,  Christos Xiouras  4 ,  Scott D Bembenek  1 ,  Richard Alexander  2 ,  Cynthia Milligan  2 ,  Sriram Balasubramanian  2 ,  Alec D Lebsack  1 ,  Jennifer D Venable  1 ,  Ulrike Philippar  4 ,  James P Edwards  1 ,  Gavin Hirst  1
Affiliations
  • 1. Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, California 92121-1126, United States.
  • 2. Janssen Research & Development, LLC, 1400 McKean Road, Spring House, Pennsylvania 19477-0776, United States.
  • 3. Janssen Research & Development, 4560 Jinke Road, Pudong New Area, Shanghai 201319, P. R. China.
  • 4. Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
PMID: 36314537 DOI: 10.1021/acs.jmedchem.2c01026
Abstract

Bruton's tyrosine kinase (Btk) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of Btk has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (13), a covalent, irreversible Btk Inhibitor with potent whole blood activity and exceptional kinome selectivity. JNJ-64264681 demonstrated excellent oral efficacy in both Cancer and autoimmune models with sustained in vivo target coverage amenable to once daily dosing and has advanced into human clinical studies to investigate safety and pharmacokinetics.

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