2. Academic Validation
  3. 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

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

  • J Med Chem. 2016 Jul 28;59(14):6690-708. doi: 10.1021/acs.jmedchem.6b00056.
Wei Yan 1,  Xinyi Wang 2 3,  Yang Dai 2,  Bin Zhao 4,  Xinying Yang 2,  Jun Fan 4,  Yinglei Gao 2,  Fanwang Meng 5 6,  Yuming Wang 4,  Cheng Luo 6,  Jing Ai 2,  Meiyu Geng 2,  Wenhu Duan 1 4
Affiliations

Affiliations

  • 1 School of Pharmacy, East China University of Science & Technology , 130 Mei Long Road, Shanghai 200237, P. R. China.
  • 2 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.
  • 3 University of Chinese Academy of Sciences , Beijing 100049, P. R. China.
  • 4 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zu Chong Zhi Road, Shanghai 201203, P. R. China.
  • 5 Department of Chemistry, College of Sciences, Shanghai University , 99 Shang Da Road, Shanghai 200444, P. R. China.
  • 6 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.
PMID: 27348537 DOI: 10.1021/acs.jmedchem.6b00056
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.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z