2. Academic Validation
  3. Design and synthesis of 1H-benzo[d]imidazole selective HDAC6 inhibitors with potential therapy for multiple myeloma

Design and synthesis of 1H-benzo[d]imidazole selective HDAC6 inhibitors with potential therapy for multiple myeloma

  • Eur J Med Chem. 2023 Sep 25:261:115833. doi: 10.1016/j.ejmech.2023.115833.
Linfu Liu 1,  Liyuan Zhang 2,  Xuxi Chen 3,  Kang Yang 2,  Hao Cui 4,  Rui Qian 3,  Shanshan Zhao 3,  Liqun Wang 3,  Xiaolan Su 5,  Manyu Zhao 3,  Mengzhu Wang 3,  Zan Hu 5,  Tao Lu 2,  Yong Zhu 2,  Qing-Qing Zhou 6,  Yuqin Yao 7
Affiliations

Affiliations

  • 1 Molecular Toxicology Laboratory of Sichuan Provincial Education Office, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, 610041, PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
  • 2 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
  • 3 Molecular Toxicology Laboratory of Sichuan Provincial Education Office, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, 610041, PR China.
  • 4 School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China; School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, PR China.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
  • 6 Department of Radiology, The Affiliated Jiangning Hospital of Nanjing Medical University, No.169, Hushan Road, Nanjing, Jiangsu, 211100, PR China; Department of Diagnostic Radiology, Jinling Hospital, Affiliated Nanjing Medical University, Nanjing, 210002, PR China. Electronic address: dzhouqingqing@163.com.
  • 7 Molecular Toxicology Laboratory of Sichuan Provincial Education Office, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, 610041, PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address: yuqin_yao@scu.edu.cn.
PMID: 37797564 DOI: 10.1016/j.ejmech.2023.115833
Abstract

Pan-HDAC inhibitors exhibit significant inhibitory activity against multiple myeloma, however, their clinical applications have been hampered by substantial toxic side effects. In contrast, selective HDAC6 inhibitors have demonstrated effectiveness in treating multiple myeloma. Compounds belonging to the class of 1H-benzo[d]imidazole hydroxamic acids have been identified as novel HDAC6 inhibitors, with the benzimidazole group serving as a specific linker for these inhibitors. Notably, compound 30 has exhibited outstanding HDAC6 inhibitory activity (IC50 = 4.63 nM) and superior antiproliferative effects against human multiple myeloma cells, specifically RPMI-8226. Moreover, it has been shown to induce cell cycle arrest in the G2 phase and promote Apoptosis through the mitochondrial pathway. In a myeloma RPMI-8226 xenograft model, compound 30 has demonstrated significant in vivo antitumor efficacy (T/C = 34.8%) when administered as a standalone drug, with no observable cytotoxicity. These findings underscore the immense potential of compound 30 as a promising therapeutic agent for the treatment of multiple myeloma.

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