2. Academic Validation
  3. Discovery of the Bruton's Tyrosine Kinase Inhibitor Clinical Candidate TAK-020 ( S)-5-(1-((1-Acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3 H-1,2,4-triazol-3-one, by Fragment-Based Drug Design

Discovery of the Bruton's Tyrosine Kinase Inhibitor Clinical Candidate TAK-020 ( S)-5-(1-((1-Acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3 H-1,2,4-triazol-3-one, by Fragment-Based Drug Design

  • J Med Chem. 2021 Sep 9;64(17):12893-12902. doi: 10.1021/acs.jmedchem.1c01026.
Mark Sabat 1,  Douglas R Dougan 1,  Beverly Knight 2,  J David Lawson 3,  Nicholas Scorah 1,  Christopher R Smith 3,  Ewan R Taylor 1,  Phong Vu 1,  Corey Wyrick 1,  Haixia Wang 1,  Deepika Balakrishna 1,  Mark Hixon 4,  Loui Madakamutil 5,  Donavon McConn 1
Affiliations

Affiliations

  • 1 Takeda California, 9625 Towne Centre Dr., San Diego, California 92121, United States.
  • 2 Pfizer, 10777 Science Center Dr., San Diego, California 92121, United States.
  • 3 Mirati Therapeutics, Inc., 9393 Towne Centre Dr. #200, San Diego, California 92121, United States.
  • 4 VeriSIM Life, 1 Sansome Street Suite 3500, San Francisco, California 94104, United States.
  • 5 Invivoscribe Therapeutics, Inc., 10222 Barnes Canyon Rd., Bldg. 1, San Diego, California 92121, United States.
PMID: 34448571 DOI: 10.1021/acs.jmedchem.1c01026
Abstract

This publication details the successful use of FBDD (fragment-based drug discovery) principles in the invention of a novel covalent Bruton's tyrosine kinase inhibitor, which ultimately became the Takeda Pharmaceuticals clinical candidate TAK-020. Described herein are the discovery of the fragment 5-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-one, the subsequent optimization of this hit molecule to the candidate, and synthesis and performance in pharmacodynamic and efficacy models along with direct biophysical comparison of TAK-020 with other clinical-level assets and the marketed drug Ibrutinib.

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