2. Academic Validation
  3. Design, synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold

Design, synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold

  • Bioorg Med Chem. 2018 Feb 1;26(3):747-757. doi: 10.1016/j.bmc.2017.12.041.
Jian Liu 1,  Chengbo Qian 2,  Yehua Zhu 2,  Jianguo Cai 2,  Yufang He 2,  Jie Li 3,  Tianlin Wang 2,  Haohao Zhu 2,  Zhi Li 2,  Wei Li 4,  Lihong Hu 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing 210023, Jiangsu, China.
  • 2 School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China.
  • 3 Pharmacy, Nanjing General Hospital, 305 Zhongshan East Road, Nanjing 210002, China.
  • 4 School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing 210023, Jiangsu, China. Electronic address: liwaii@126.com.
  • 5 School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China; Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing 210023, Jiangsu, China; Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
PMID: 29317150 DOI: 10.1016/j.bmc.2017.12.041
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 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 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.

Keywords

1H-Indazol-3-amine and benzohydroxamic acids hybrids; Dual inhibitor; FGFR1; HDACs; MCF-7.

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