Design, Synthesis and Evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold

Publication date: Available online 29 December 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Jian Liu, Chengbo Qian, Yehua Zhu, Jianguo Cai, Yufang He, Jie Li, Tianlin Wang, Haohao Zhu, Zhi Li, Wei Li, Lihong Hu
Both Histone deacetylase (HDAC) and Fibroblast growth factor receptor (FGFR) are important targets for cancer therapy. Although combining dual HDAC pharmacophore with tyrosine kinase inhibitors (TKIs) had achieved a successful progress, dual HDAC/FGFR1 inhibitors haven't been reported yet. Herein, we designed a series of hybrids bearing 1H-indazol-3-amine and benzohydroxamic acids scaffold with scaffold hopping and molecular hybridization strategies. Among them, compound 7j showed the most potent inhibitory activity against HDAC6 with IC50 of 34nM and exhibited the great inhibitory activities against a human breast cancer cell line MCF-7 with IC50 of 9 μM in vitro. Meanwhile, the compound also exhibited moderate FGFR1 inhibitory activities. This study provides new tool compounds for further exploration of dual HDAC/FGFR1 inhibition.

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