Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China.
Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
Chem Res Toxicol. 2024 Jun 17;37(6):1062-1069. doi: 10.1021/acs.chemrestox.4c00142. Epub 2024 May 30.
Multiple myeloma is a hematological cancer that can be treated but remains incurable. With the advancement of science and technology, more drugs have been developed for myeloma chemotherapy that greatly improve the quality of life of patients. However, relapse remains a serious problem puzzling patients and doctors. Thus, developing more highly active and specific inhibitors is urgent for myeloma-targeted therapy. In this study, we identified the SIRT3 inhibitor 3-TYP (3-(1-1,2,3-triazol-4-yl) pyridine) after screening a histone modification compound library, which showed high cytotoxicity and induced DNA damage in myeloma cells. Furthermore, the inhibitory effect of 3-TYP in our xenograft tumor studies also confirmed that compound 3-TYP could inhibit primary myeloma growth by reducing c-Myc protein stability by decreasing c-Myc Ser62 phosphorylation levels. Taken together, the results of our study identified 3-TYP as a novel c-Myc inhibitor, which could be a potential chemotherapeutic agent to target multiple myeloma.
多发性骨髓瘤是一种血液系统癌症，可以治疗但无法治愈。随着科学技术的进步，已经开发出更多用于多发性骨髓瘤化疗的药物，大大提高了患者的生活质量。然而，复发仍然是一个令患者和医生困惑的严重问题。因此，开发更高效和更特异的抑制剂对于多发性骨髓瘤的靶向治疗非常紧迫。在这项研究中，我们在筛选组蛋白修饰化合物库后鉴定出 SIRT3 抑制剂 3-TYP（3-(1-1,2,3-三唑-4-基)吡啶），它对骨髓瘤细胞表现出高细胞毒性并诱导 DNA 损伤。此外，我们在异种移植肿瘤研究中的抑制作用也证实，化合物 3-TYP 可以通过降低 c-Myc Ser62 磷酸化水平来减少 c-Myc 蛋白稳定性，从而抑制原代骨髓瘤的生长。总之，我们的研究结果鉴定出 3-TYP 是一种新型的 c-Myc 抑制剂，它可能成为治疗多发性骨髓瘤的潜在化疗药物。
