Abstract
Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is a promising target for cancer therapy. Here we reported the design, synthesis, and biological evaluation of a new series of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazole derivatives as potent FGFR inhibitors. The compound 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-phenyl-1H-indazole-4-carboxamide (10a) was identified as a potent FGFR1 inhibitor, with good enzymatic inhibition. Further structure-based optimization revealed that 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-4-carboxamide (13a) is the most potent FGFR1 inhibitor in this series, with an enzyme inhibitory activity IC50 value of about 30.2 nM.
Highlights
Fibroblast growth factor receptors (FGFRs), consisting of the four members FGFR1-4, belong to the family of receptor tyrosine kinases (RTKs) and play fundamental roles in several basic biological processes, including tissue development, angiogenesis and tissue regeneration [1–3].Overactivation of fibroblast growth factor receptor (FGFR) signaling occurs in many types of cancer due to gene amplification, mutations or translocations [4–7]
FGFR has been validated as an attractive target for targeted cancer therapy [8,12–14]
Simultaneous inhibition of multiple RTKs may reinforce the efficacy in patients by concomitant disturbance of redundant pathways, it may increase the chance of side effects or severe toxicity [17,18]
Summary
Overactivation of FGFR signaling occurs in many types of cancer due to gene amplification, mutations or translocations [4–7]. Aberrant FGFR signaling drives oncogenic growth of tumor subsets, especially those lacking effective treatments, such as 20% squamous non-small cell lung carcinoma and 4%. FGFR has been validated as an attractive target for targeted cancer therapy [8,12–14]. Several small molecule FGFR inhibitors have been reported, and some of them are in clinical trials [15]. The early examples of FGFR inhibitors are predominantly multi-targeting drugs, such as nintedanib, lenvatinib, dovitinib, and lucitanib [16]. Simultaneous inhibition of multiple RTKs may reinforce the efficacy in patients by concomitant disturbance of redundant pathways, it may increase the chance of side effects or severe toxicity [17,18]. Discovery of potent and selective FGFR inhibitors is an urgent need in cancer treatment.
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