2. Academic Validation
  3. Design and synthesis of highly TRAIL expression HDAC inhibitors based on ONC201 to promote apoptosis of colorectal cancer

Design and synthesis of highly TRAIL expression HDAC inhibitors based on ONC201 to promote apoptosis of colorectal cancer

  • Eur J Med Chem. 2022 Aug 5:238:114484. doi: 10.1016/j.ejmech.2022.114484.
Hao Cui 1,  Zan Hu 2,  Kang Yang 1,  Jingkun Huang 1,  Yichao Wu 1,  Quanwei Chen 1,  Ran Wei 1,  Penfeng Wang 1,  Hui Wang 1,  Hongmei Li 1,  Yadong Chen 1,  Tao Lu 3,  Yuqin Yao 4,  Yong Zhu 5
Affiliations

Affiliations

  • 1 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West, Sichuan University, Chengdu, 610041, China.
  • 3 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: lutao@cpu.edu.cn.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West, Sichuan University, Chengdu, 610041, China; West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: yuqin_yao@scu.edu.cn.
  • 5 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address: zhuyong@cpu.edu.cn.
PMID: 35649291 DOI: 10.1016/j.ejmech.2022.114484
Abstract

Activation of the TRAIL proapoptotic pathway can promote Cancer cell Apoptosis. Histone deacetylases (HDACs) also are promising drug targets for cancers, and their synergistic effect with TRAIL can improve the inhibitory effect on Cancer cells. Therefore, the development of highly TRAIL-sensitive HDAC inhibitors might be a promising strategy for the treatment of cancers. We synthesized a series of HDAC inhibitors by introducing effective fragments sensitive to TRAIL. Compound IIc showed good inhibitory activity against HDAC1 and HCT116 cells and showed higher sensitivity to activating the expression of the TRAIL protein and promoting the Apoptosis of HCT-116 cells compared with ONC201. The inhibitory activity of compound IIc (25 mg/kg) in the HCT-116 xenograft model was significantly greater than those of the positive control drugs (ONC201, chidamide). These findings suggested that development of highly TRAIL-sensitive HDAC inhibitors as colorectal tumor Cancer drugs.

Keywords

Apoptosis; HDACs; Sensitive; TRAIL.

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