SPC-180002是一种SIRT1/3双重抑制剂，它破坏了线粒体功能和氧化还原平衡，具有抗肿瘤活性。
SPC-180002, a SIRT1/3 dual inhibitor, impairs mitochondrial function and redox homeostasis and represents an antitumor activity.
发表日期：2023 Aug 01
作者：
Yena Cho, Jee Won Hwang, No-June Park, Junghyea Moon, Khan Hashim Ali, Young Ho Seo, In Su Kim, Su-Nam Kim, Yong Kee Kim
来源：
ANTIOXIDANTS & REDOX SIGNALING
摘要：
由于sirtuins（SIRTs）与活性氧（ROS）和抗氧化系统密切相关，开发其选择性抑制剂引起了对细胞氧化还原平衡理解的关注。在这里，我们描述了SPC-180002的药理特性，该化合物以甲基丙烯酸甲酯基团作为关键药效团，并详细阐述了其作为SIRT1/3的新型双重抑制剂的分子机制。SPC-180002通过双重抑制SIRT1/3扰乱了氧化还原平衡，导致ROS产生增加，进而增加p21蛋白的稳定性和线粒体功能障碍。p21的增加与抑制CDK相互作用，从而干扰细胞周期进程。SPC-180002通过抑制线粒体自噬导致线粒体功能紊乱，伴随氧耗速率的降低。因此，SPC-180002强烈抑制癌细胞的增殖，并在体内展现抗癌效果。综上所述，新型SIRT1/3双重抑制剂SPC-180002损害了线粒体功能和氧化还原平衡，从而强烈抑制了细胞周期进程和癌细胞生长。版权所有 © 2023 Elsevier Inc.
Since sirtuins (SIRTs) are closely associated with reactive oxygen species (ROS) and antioxidant system, the development of their selective inhibitors is drawing attention for understanding of cellular redox homeostasis. Here, we describe the pharmacological properties of SPC-180002, which incorporates a methyl methacrylate group as a key pharmacophore, along with its comprehensive molecular mechanism as a novel dual inhibitor of SIRT1/3. The dual inhibition of SIRT1/3 by SPC-180002 disturbs redox homeostasis via ROS generation, which leads to an increase in both p21 protein stability and mitochondrial dysfunction. Increased p21 interacts with and inhibits CDK, thereby interfering with cell cycle progression. SPC-180002 leads to mitochondrial dysfunction by inhibiting mitophagy, which is accompanied by a reduction in oxygen consumption rate. Consequently, SPC-180002 strongly suppresses the proliferation of cancer cells and exerts anticancer effect in vivo. Taken together, the novel SIRT1/3 dual inhibitor, SPC-180002, impairs mitochondrial function and redox homeostasis, thereby strongly inhibiting cell cycle progression and cancer cell growth.Copyright © 2023. Published by Elsevier Inc.