2. Academic Validation
  3. Optimization of 1H-indazol-3-amine derivatives as potent fibroblast growth factor receptor inhibitors

Optimization of 1H-indazol-3-amine derivatives as potent fibroblast growth factor receptor inhibitors

  • Bioorg Med Chem Lett. 2017 Aug 15;27(16):3782-3786. doi: 10.1016/j.bmcl.2017.06.068.
Jing Cui 1,  Xia Peng 2,  Dingding Gao 1,  Yang Dai 2,  Jing Ai 3,  Yingxia Li 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China.
  • 2 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 3 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: jai@simm.ac.cn.
  • 4 School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: liyx417@fudan.edu.cn.
PMID: 28687204 DOI: 10.1016/j.bmcl.2017.06.068
Abstract

Fibroblast Growth Factor receptor (FGFR) is a potential target for Cancer therapy because of its critical role in promoting Cancer formation and progression. In a continuing effort to improve the cellular activity of hit compound 7r bearing an indazole scaffold, which was previously discovered by our group, several compounds harnessing fluorine substituents were designed, synthesized and biological evaluated. Besides, the region extended out to the ATP binding pocket toward solvent was also explored. Among them, compound 2a containing 2,6-difluoro-3-methoxyphenyl residue exhibited the most potent activities (FGFR1: less than 4.1nM, FGFR2: 2.0±0.8nM). More importantly, compound 2a showed an improved antiproliferative effect against KG1 cell lines and SNU16 cell lines with IC50 values of 25.3±4.6nM and 77.4±6.2nM respectively.

Keywords

Cellular activity; FGFR; Fluorine; Inhibitors.

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