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

Ken A Brameld; Timothy D Owens; Erik Verner; Eleni Venetsanakos; J Michael Bradshaw; Vernon T Phan; Danny Tam; Kwan Leung; Jin Shu; Jacob LaStant; David G Loughhead; Tony Ton; Dane E Karr; Mary E Gerritsen; David M Goldstein; Jens Oliver Funk

doi:10.1021/acs.jmedchem.7b00360

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. Epub 2017 Jul 25.

Authors

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.

MeSH terms

Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Dogs
Drug Design
Drug Stability
Female
Humans
Intestinal Absorption
Macaca fascicularis
Male
Neoplasms / drug therapy*
Pyridones / administration & dosage
Pyridones / chemical synthesis
Pyridones / pharmacokinetics
Pyridones / pharmacology*
Pyrimidines / administration & dosage
Pyrimidines / chemical synthesis
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology*
Rats, Sprague-Dawley
Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 3 / antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors
Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
Solubility
Structure-Activity Relationship

Substances

Antineoplastic Agents
PRN1371
Pyridones
Pyrimidines
Receptors, Fibroblast Growth Factor
Receptor, Fibroblast Growth Factor, Type 1
Receptor, Fibroblast Growth Factor, Type 2
Receptor, Fibroblast Growth Factor, Type 3
Receptor, Fibroblast Growth Factor, Type 4