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.

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.
Authors	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
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 60 Issue 15 Pg. 6516-6527 (08 10 2017) ISSN: 1520-4804 [Electronic] United States
PMID	28665128 (Publication Type: Journal Article)
Chemical References	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
Topics	Animals Antineoplastic Agents (administration & dosage, chemical synthesis, pharmacokinetics, pharmacology) Cell Line, Tumor Dogs Drug Design Drug Stability Female Humans Intestinal Absorption Macaca fascicularis Male Neoplasms (drug therapy) Pyridones (administration & dosage, chemical synthesis, pharmacokinetics, pharmacology) Pyrimidines (administration & dosage, chemical synthesis, pharmacokinetics, 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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!