2. Academic Validation
  3. A new BET inhibitor, 171, inhibits tumor growth through cell proliferation inhibition more than apoptosis induction

A new BET inhibitor, 171, inhibits tumor growth through cell proliferation inhibition more than apoptosis induction

  • Invest New Drugs. 2020 Jun;38(3):700-713. doi: 10.1007/s10637-019-00818-z.
Mohammadali Soleimani Damaneh 1 2,  Jian-Ping Hu 3,  Xia-Juan Huan 1,  Shan-Shan Song 1,  Chang-Qing Tian 1 2,  Dan-Qi Chen 3,  Tao Meng 3,  Yue-Lei Chen 3,  Jing-Kang Shen 3,  Bing Xiong 4,  Ze-Hong Miao 5 6 7,  Ying-Qing Wang 8 9
Affiliations

Affiliations

  • 1 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China.
  • 3 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. bxiong@simm.ac.cn.
  • 5 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. zhmiao@simm.ac.cn.
  • 6 University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China. zhmiao@simm.ac.cn.
  • 7 Open Studio for Drugability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Shandong, 266237, China. zhmiao@simm.ac.cn.
  • 8 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. yqwang@simm.ac.cn.
  • 9 University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China. yqwang@simm.ac.cn.
PMID: 31267379 DOI: 10.1007/s10637-019-00818-z
Abstract

The bromodomain and extra-terminal domain (BET) family of proteins, especially bromodomain-containing protein 4 (BRD4), has emerged as exciting anti-tumor targets due to their important roles in epigenetic regulation. Therefore, the discovery of BET inhibitors with promising anti-tumor efficacy will provide a novel approach to epigenetic Anticancer therapy. Recently, we discovered the new BET inhibitor compound 171, which is derived from a polo-like kinase 1 (PLK1)-BRD4 dual inhibitor based on our previous research. Compound 171 was found to maintain BET inhibition ability without PLK1 inhibition, and there was no selectivity among BET family members. The in vitro and in vivo results both indicated that the overall anti-tumor activity of compound 171 was improved compared with the (+)-JQ-1 or OTX-015 BET inhibitors. Furthermore, we found that compound 171 could regulate the expression of cell cycle-regulating proteins including c-Myc and p21 and induce cell cycle arrest in the G0/G1 phase. However, compound 171 only has a quite limited effect on Apoptosis, in considering that Apoptosis was only observed at doses greater than 50 μM. To determine the mechanisms underlying cell death, proliferation activity assay was conducted. The results showed that compound 171 induced clear anti-proliferative effects at doses that no obvious Apoptosis was induced, which indicated that the cell cycle arresting effect contributed mostly to its anti-tumor activity. The result of this study revealed the anti-tumor mechanism of compound 171, and laid a foundation for the combination therapy in clinical practice, if compound 171 or its series compounds become drug candidates in the future.

Keywords

Anti-cancer agent; Apoptosis; BET inhibitor; Cell proliferation.

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