2. Academic Validation
  3. Synthesis and biological evaluation of novel pyrazole amides as potent mitochondrial complex I inhibitors

Synthesis and biological evaluation of novel pyrazole amides as potent mitochondrial complex I inhibitors

  • Eur J Med Chem. 2023 Oct 5;258:115576. doi: 10.1016/j.ejmech.2023.115576.
Yang Zhou 1,  Jiao Zou 1,  Xi Zhong 2,  Jing Xu 1,  Kun Gou 1,  Xia Zhou 1,  Yue Zhou 1,  Xinyu Yang 2,  Xinqi Guan 1,  Yu Zhang 3,  Donglin Chen 2,  Xiaobo Cen 4,  Youfu Luo 5,  Yinglan Zhao 6
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
  • 3 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; School of Medicine, Tibet University, Lhasa, 850000, China.
  • 4 National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 5 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 6 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 37392582 DOI: 10.1016/j.ejmech.2023.115576
Abstract

Targeting mitochondrial complex I (CI) is emerging as an attractive Anticancer strategy, and CI inhibitor IACS-010759 has achieved breakthrough success. However, the narrow therapeutic index of IACS-010759 seriously hinders its further application. In this study, a series of novel pyrazole amides were designed and optimized based on IACS-010759, and their potential CI inhibitory effects were biologically evaluated. Among them, the maximum tolerated dose (MTD) values of SCAL-255 (compound 5q) and SCAL-266 (compound 6f) were 68 mg/kg, which was nearly 10 times that of IACS-010759 (6 mg/kg), showing good safety. In addition, SCAL-255 and SCAL-266 significantly inhibited the proliferation of HCT116 and KG-1 cells in vitro and exerted satisfactory inhibitory activity against KG-1 cells in vivo. These results suggested that the optimized compounds might serve as promising CI inhibitors against oxidative phosphorylation (OXPHOS)-dependent Cancer, which merits further study.

Keywords

Antitumor; Mitochondrial complex I; Pyrazole amides.

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