title: 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.affiliation: School of Pharmacy, East China University of Science & Technology , 130 Mei Long Road, Shanghai 200237, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.|University of Chinese Academy of Sciences , Beijing 100049, P. R. China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
authors.forename: Yinglei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Chemistry, College of Sciences, Shanghai University , 99 Shang Da Road, Shanghai 200444, P. R. China.|Drug Discovery & Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
authors.forename: Fanwang
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Drug Discovery & Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.affiliation: School of Pharmacy, East China University of Science & Technology , 130 Mei Long Road, Shanghai 200237, P. R. China.|Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
authors.forename: Wenhu
authors.initials: W
authors.lastname: Duan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007191:Indazoles; D017468:Receptors, Fibroblast Growth Factor; C000619735:benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole