Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.
College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, United States.
J Med Chem. 2024 Sep 12;67(17):15428-15437. doi: 10.1021/acs.jmedchem.4c01053. Epub 2024 Aug 27.
Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous cancers that still require better and less toxic treatments. SIRT3, a member of the sirtuin family of NAD-dependent protein deacylase, is critical for DLBCL growth and survival. A mitochondria-targeted SIRT3 small-molecule inhibitor, YC8-02, exhibits promising activity against DLBCL. However, YC8-02 has several limitations including poor solubility. Here, we report our medicinal chemistry efforts that led to an improved mitochondria-targeted SIRT3 inhibitor, SJ-106C, achieved by using a triethylammonium group, which helps to increase both solubility and SIRT3 inhibition potency. SJ-106C, while still inhibiting SIRT1 and SIRT2, is enriched in the mitochondria to help with SIRT3 inhibition. It is more active against DLBCL than other solid tumor cells and effectively inhibits DLBCL xenograft tumor growth. The findings provide useful insights for the development of SIRT3 inhibitors and mitochondrial targeting agents and further support the notion that SIRT3 is a promising druggable target for DLBCL.
弥漫性大 B 细胞淋巴瘤 (DLBCLs) 是一种异质性癌症，仍需要更好、毒性更低的治疗方法。SIRT3 是 NAD 依赖性蛋白去乙酰化酶家族的成员，对 DLBCL 的生长和存活至关重要。一种靶向线粒体的 SIRT3 小分子抑制剂 YC8-02 对 DLBCL 表现出有前景的活性。然而，YC8-02 存在几个局限性，包括溶解度差。在这里，我们报告了我们的药物化学努力，通过使用三乙铵基团，得到了一种改进的靶向线粒体的 SIRT3 抑制剂 SJ-106C，这有助于提高溶解度和 SIRT3 抑制活性。SJ-106C 虽然仍然抑制 SIRT1 和 SIRT2，但在线粒体中富集，有助于 SIRT3 的抑制。它对 DLBCL 的活性高于其他实体瘤细胞，并能有效抑制 DLBCL 异种移植肿瘤的生长。这些发现为 SIRT3 抑制剂和线粒体靶向剂的开发提供了有用的见解，并进一步支持了 SIRT3 是 DLBCL 有前途的可药物靶点的观点。
