Discovery of Novel SIRT3 Inhibitors for the Cancer Differentiation Therapy by Structural Modification

IF 3.5 4区医学 Q2 CHEMISTRY, MEDICINAL

Drug Development Research Pub Date : 2024-11-11 DOI:10.1002/ddr.70016

Honggang Li, Yanmei Du, Lihui Zhang, Guangzhao Xu, Fahui Li, Daopeng Zhang, Lei Zhang

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引用次数: 0

Abstract

Inhibition of SIRT3 triggered differentiation of multiple myeloma (MM) cells. In discovery of potent SIRT3 inhibitors for cancer differentiation therapy, structural modification was performed on the previously developed lead compound S27. A total of 49 compounds divided into two series were designed and synthesized. In the enzyme inhibitory assay, several molecules (A7, A13, B15, and B26) exhibited potent SIRT3 inhibitory activity and selectivity. Significantly, representative compounds, especially A7, promoted differentiation of MM cells from cancer phenotype to normal cells, accompanied by increased expression of antigen CD49e, human immunoglobulin light chain λ-IgLG and κ-IgLG. Additionally, molecule A7 reversed growth factor IL-6 induced MM cell proliferation, improved the antiproliferative activity of Ixazomib and increased the apoptotic rate of MM cells treated with Ixazomib. Collectively, potent SIRT3 inhibitors with MM cell differentiation potency were developed for the cancer therapy used alone or in combination.

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通过结构改造发现用于癌症分化治疗的新型 SIRT3 抑制剂

抑制 SIRT3 会引发多发性骨髓瘤（MM）细胞的分化。为了发现用于癌症分化治疗的强效 SIRT3 抑制剂，我们对之前开发的先导化合物 S27 进行了结构改造。共设计并合成了 49 个化合物，分为两个系列。在酶抑制实验中，几个分子（A7、A13、B15 和 B26）表现出了强效的 SIRT3 抑制活性和选择性。值得注意的是，代表性化合物，尤其是 A7，能促进 MM 细胞从癌症表型向正常细胞分化，同时增加抗原 CD49e、人免疫球蛋白轻链 λ-IgLG 和 κ-IgLG 的表达。此外，分子 A7 还能逆转生长因子 IL-6 诱导的 MM 细胞增殖，提高伊沙佐米的抗增殖活性，并增加接受伊沙佐米治疗的 MM 细胞的凋亡率。总之，我们开发出了具有 MM 细胞分化效力的强效 SIRT3 抑制剂，可单独或联合用于癌症治疗。

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来源期刊

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.