Discovery of 3-(5'-Substituted)-Benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors: Design, Synthesis, and Biological Evaluation.

Abstract	Fibroblast growth factor receptor (FGFR) represents an attractive oncology target for cancer therapy in view of its critical role in promoting cancer formation and progression, as well as causing resistance to approved therapies. In this article, we describe the identification of the potent pan-FGFR inhibitor (R)-21c (FGFR1-4 IC50 values of 0.9, 2.0, 2.0, and 6.1 nM, respectively). Compound (R)-21c exhibited excellent in vitro inhibitory activity against a panel of FGFR-amplified cell lines. Western blot analysis demonstrated that (R)-21c suppressed FGF/FGFR and downstream signaling pathways at nanomolar concentrations. Moreover, (R)-21c provided nearly complete inhibition of tumor growth (96.9% TGI) in NCI-H1581 (FGFR1-amplified) xenograft mice model at the dose of 10 mg/kg/qd via oral administration.
Authors	Wei Yan, Xinyi Wang, Yang Dai, Bin Zhao, Xinying Yang, Jun Fan, Yinglei Gao, Fanwang Meng, Yuming Wang, Cheng Luo, Jing Ai, Meiyu Geng, Wenhu Duan
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 59 Issue 14 Pg. 6690-708 (07 28 2016) ISSN: 1520-4804 [Electronic] United States
PMID	27348537 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Benzimidazoles Indazoles Receptors, Fibroblast Growth Factor benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole
Topics	Animals Antineoplastic Agents (administration & dosage, chemistry, pharmacology) Benzimidazoles (chemical synthesis, chemistry, pharmacology) Cell Line, Tumor Cell Proliferation (drug effects) Dose-Response Relationship, Drug Drug Discovery Female Humans Indazoles (chemical synthesis, chemistry, pharmacology) Mice Mice, Nude Models, Molecular Molecular Structure Neoplasms, Experimental (drug therapy, pathology) Receptors, Fibroblast Growth Factor (antagonists & inhibitors) Structure-Activity Relationship Xenograft Model Antitumor Assays

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!