2. Academic Validation
  3. Design, synthesis and biological evaluation of novel SIRT3 inhibitors targeting both NAD+ and substrate binding sites for the treatment of acute myeloid leukemia

Design, synthesis and biological evaluation of novel SIRT3 inhibitors targeting both NAD+ and substrate binding sites for the treatment of acute myeloid leukemia

  • Eur J Med Chem. 2024 Oct 5:276:116689. doi: 10.1016/j.ejmech.2024.116689.
Xuetao Yang 1,  Ge Ge 2,  Hailing Wang 2,  Tianli Liu 1,  Dabo Pan 3,  Xi Zhao 2,  Xiya Chen 2,  Jinhui Wang 4,  Jin Zhang 5,  Ke Zhang 6,  Dahong Yao 7
Affiliations

Affiliations

  • 1 Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy, Shihezi University, Shihezi, 832002, China; School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518118, China.
  • 2 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518055, China; School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518118, China.
  • 3 Department of Medical Technology, Qiandongnan Vocational & Technical College for Nationalities, Kaili, 556000, China.
  • 4 Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy, Shihezi University, Shihezi, 832002, China.
  • 5 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518055, China. Electronic address: zhangjin1989@szu.edu.cn.
  • 6 Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy, Shihezi University, Shihezi, 832002, China. Electronic address: tcm_zk@163.com.
  • 7 School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518118, China. Electronic address: yaodahong@sztu.edu.cn.
PMID: 39053191 DOI: 10.1016/j.ejmech.2024.116689
Abstract

Acute myeloid leukemia (AML) represents a highly malignant subtype of leukemia with limited therapeutic options. In this study, we propose a novel therapeutic strategy for treating AML by inhibiting SIRT3 to regulate Mitochondrial Metabolism network involved in energy metabolism and epigenetic modifications essential for AML survival. A series of thieno [3,2-d]pyrimidine-6-carboxamide derivatives were designed and synthesized by structure-based strategy, 17f was documented to be a potent and acceptable selective SIRT3 Inhibitor with IC50 value of 0.043 μM and exhibited profound anti-proliferative activity in MOLM13, MV4-11, and HL-60 cells. Through CETSA assay and the degree of deacetylation of intracellular SIRT3 substrates, we confirmed that 17f could effectively bind and inhibit SIRT3 activity in AML cells. Mechanistically, 17f suppressed mitochondrial function, triggered the accumulation of ROS, and significantly inhibited the production of ATP in AML cells. With the breakdown of mitochondrial function, 17f eventually induced Apoptosis of AML cells. In addition, 17f also showed excellent anti-AML potential in nude mouse tumor models of HL-60-Luc. Collectively, these results demonstrate that 17f is a potent and acceptable selective SIRT3 Inhibitor with promising potential to treat AML.

Keywords

AML; Apoptosis; Mitochondrial metabolism; SIRT3.

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