Cho, Yena Hwang, Jee Won Park, No-June Moon, Junghyea Ali, Khan Hashim Seo, Young Ho Kim, In Su Kim, Su-Nam Kee, Yong 2024-01-19T08:30:49Z 2024-01-19T08:30:49Z 2023-09-21 2023-11 0891-5849 https://pubs.kist.re.kr/handle/201004/113147 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. English Elsevier BV SPC-180002, a SIRT1/3 dual inhibitor, impairs mitochondrial function and redox homeostasis and represents an antitumor activity Article 10.1016/j.freeradbiomed.2023.07.033 1 Free Radical Biology and Medicine, v.208, pp.73 - 87 Free Radical Biology and Medicine 208 73 87 N scie scopus 001059473900001 2-s2.0-85166764256 Biochemistry & Molecular Biology Endocrinology & Metabolism Biochemistry & Molecular Biology Endocrinology & Metabolism Article ACTIVATED PROTEIN-KINASE FOXO TRANSCRIPTION FACTORS DIRECT PHOSPHORYLATION CELL-DEATH STRESS CANCER AMPK DEACETYLATION ACETYLATION METABOLISM SIRT1/3 dual inhibitor SPC-180002 Mitochondrial dynamics Cellular respiration Redox homeostasis Mitophagy