Article

SOMCL-085, a novel multi-targeted FGFR inhibitor, displays potent anticancer activity in FGFR-addicted human cancer models

Authors: Xi-fei JIANG1, Yang DAI2, Xia PENG2, Yan-yan SHEN2, Yi SU2, Man-man WEI3, Wei-ren LIU1, Zhen-bin DING1, Ao ZHANG2, Ying-hong SHI1, Jing AI2
1 Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai 200032, China
2 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3 CAS Key Laboratory of Receptor Research, and Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Corresponding to: Ying-hong SHI: shi.yinghong@zs-hospital.sh.cn, Jing AI: jai@simm.ac.cn,
DOI: 10.1038/aps.2017.96
Received: 24 May 2017
Accepted: 20 June 2017
Advance online: 14 September 2017

Abstract

Abstract
Aberrant fibroblast growth factor receptor (FGFR) activation is found across a diverse spectrum of malignancies, especially those lacking effective treatments. SOMCL-085 is a novel FGFR-dominant multi-target kinase inhibitor. Here, we explored the FGFRtargeting anticancer activity of SOMCL-085 both in vitro and in vivo. Among a panel of 20 tyrosine kinases screened, SOMCL-085 potently inhibited FGFR1, FGFR2 and FGFR3 kinase activity, with IC50 values of 1.8, 1.9 and 6.9 nmol/L, respectively. This compound simultaneously inhibited the angiogenesis kinases VEGFR and PDGFR, but without obvious inhibitory effect on other 12 tyrosine kinases. In 3 representative human cancer cell lines with different mechanisms of FGFR activation tested, SOMCL-085 (20–500 nmol/L) dose-dependently inhibited FGFR1-3 phosphorylation and the phosphorylation of their key downstream effectors PLCγ and Erk. In 7 FGFR aberrant human cancer cell lines, regardless of the mechanistic complexity of FGFR over-activation, SOMCL-085 potently inhibited FGFR-driven cell proliferation by arresting cells at the G1/S phase. In the FGFR1-amplified lung cancer cell line H1581 xenograft mice and FGFR2-amplified gastric cancer cell line SNU16 xenograft mice, oral administration of SOMCL-085 (25, 50 mg·kg-1·d-1) for 21 days substantially suppressed tumor growth without affecting their body-weight. These results suggest that SOMCL- 085 is a potent multi-target FGFR inhibitor that inhibits the FGFR-dependent neoplastic phenotypes of human cancer cells in vitro and in vivo.
Keywords: human cancer; anticancer drug; SOMCL-085; receptor tyrosine kinase; FGFR; xenograft nude mouse model