Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid Tumors

  • J Med Chem. 2017 Aug 10;60(15):6516-6527. doi: 10.1021/acs.jmedchem.7b00360.
Ken A Brameld  1 ,  Timothy D Owens  1 ,  Erik Verner  1 ,  Eleni Venetsanakos  1 ,  J Michael Bradshaw  1 ,  Vernon T Phan  1 ,  Danny Tam  1 ,  Kwan Leung  1 ,  Jin Shu  1 ,  Jacob LaStant  1 ,  David G Loughhead  1 ,  Tony Ton  1 ,  Dane E Karr  1 ,  Mary E Gerritsen  1 ,  David M Goldstein  1 ,  Jens Oliver Funk  1
Affiliations
  • 1. Principia Biopharma, Inc. , 400 East Jamie Court, South San Francisco, California 94080, United States.
PMID: 28665128 DOI: 10.1021/acs.jmedchem.7b00360
Abstract

Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1-4 for use in oncology indications. An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition. Herein we report the structure-based design, medicinal chemistry optimization, and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compound 34 (PRN1371), a highly selective and potent FGFR1-4 inhibitor.

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