Design, synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold. Issue 3 (1st February 2018)

• Record Type: Journal Article
• Authors: Liu, Jian; Qian, Chengbo; Zhu, Yehua; Cai, Jianguo; He, Yufang; Li, Jie; Wang, Tianlin; Zhu, Haohao; Li, Zhi; Li, Wei; Hu, Lihong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 3(2018)
• Page Start: 747
• Page End: 757
• Publication Date: 2018-02-01
• Subjects: 1H-Indazol-3-amine and benzohydroxamic acids hybrids -- HDACs -- FGFR1 -- Dual inhibitor -- MCF-7; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.12.041
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 1 H -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 34 nM 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.