2. Academic Validation
  3. Design, synthesis and biological evaluation of novel indazole-based derivatives as potent HDAC inhibitors via fragment-based virtual screening

Design, synthesis and biological evaluation of novel indazole-based derivatives as potent HDAC inhibitors via fragment-based virtual screening

  • Eur J Med Chem. 2020 Apr 15:192:112189. doi: 10.1016/j.ejmech.2020.112189.
Jian Liu 1,  Jingxian Zhou 2,  Fengjun He 2,  Liang Gao 2,  Yu Wen 2,  Lina Gao 2,  Ping Wang 2,  Di Kang 3,  Lihong Hu 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: liujian623@njucm.edu.cn.
  • 2 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
  • 3 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: kangdi@njucm.edu.cn.
  • 4 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Stake Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China. Electronic address: lhhu@njucm.edu.cn.
PMID: 32151834 DOI: 10.1016/j.ejmech.2020.112189
Abstract

Based on fragment-based virtual screening and bioisoterism strategies, novel indazole and pyrazolo[3,4-b] pyridine derivatives as HDACs inhibitors were designed, synthesized and evaluated. Most of these compounds displayed good to excellent inhibitory activities against HDACs, especially compounds 15k and 15m were identified as potent inhibitors of HDAC1 (IC50 = 2.7 nM and IC50 = 3.1 nM), HDAC2 (IC50 = 4.2 nM and IC50 = 3.6 nM) and HDAC8 (IC50 = 3.6 nM and IC50 = 3.3 nM). Further anti-proliferation assays revealed that compounds 15k and 15m showed better anti-proliferative activities against HCT-116 and HeLa cells than positive control SAHA. The western blot analysis results indicated that compounds 15k and 15m noticeably up-regulated the level of acetylated α-tubulin and histone H3. In addition, the two compounds 15k and 15m could arrest cell cycle in G2/M phase and promote cell Apoptosis, which was similar as the reference compound SAHA. Through the molecular docking and dynamic studies, the potent HDAC inhibitory activities mainly caused by van der Waals and electrostatic interactions with the HDACs.

Keywords

Antitumor activity; Fragment-based drug design; HDAC; HDAC inhibitors; Indazole scaffold.

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