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

• 来源期刊: 中国药理学报（英文版）
• 关键词: human cancer anticancer drug SOMCL-085 receptor tyrosine kinase FGFR xenograft nude mouse model
• 年，卷（期）: 2018,（2）
• 页码范围: 243-250
• 页数: 8页
• 语种: 英文
• DOI: 10.1038/aps.2017.96

摘要

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 FGFR-targeting 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 PLCy 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.