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
| Autor: | Mary E. Gerritsen, Dane Karr, Ken A. Brameld, Timothy D. Owens, Vernon T. Phan, Jens Oliver Funk, Eleni Venetsanakos, David G. Loughhead, Tony Ton, Danny Tam, David Michael Goldstein, Erik Verner, Jin Shu, Kwan Leung, Jacob LaStant, J. Michael Bradshaw |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Pyridones Antineoplastic Agents Pharmacology Intestinal absorption Rats Sprague-Dawley Structure-Activity Relationship 03 medical and health sciences Dogs 0302 clinical medicine Drug Stability Cell Line Tumor Neoplasms Drug Discovery Animals Humans Receptor Fibroblast Growth Factor Type 3 Structure–activity relationship Receptor Fibroblast Growth Factor Type 4 Receptor Fibroblast Growth Factor Type 1 Receptor Fibroblast Growth Factor Type 2 Receptor ADME Chemistry Drug discovery Receptors Fibroblast Growth Factor Macaca fascicularis Pyrimidines 030104 developmental biology Intestinal Absorption Solubility Cell culture Covalent bond Fibroblast growth factor receptor Drug Design 030220 oncology & carcinogenesis Molecular Medicine Female |
| Zdroj: | Journal of Medicinal Chemistry. 60:6516-6527 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b00360 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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