2. Academic Validation
  3. 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

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

Affiliation

  • 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101768
    99.43%, FGFR Inhibitor