Son, Youngchai Su, Yang Ji Shin, Sang Chul Park Seo Kyoung Kim, Yeojin Park, Jinyoung Yu, Jinha 2024-03-04T02:30:08Z 2024-03-04T02:30:08Z 2024-02-29 2024-04 0045-2068 https://pubs.kist.re.kr/handle/201004/149389 Ubiquitination is a representative post-translational modification that tags target proteins with ubiquitin to induce protein degradation or modify their functions. Deubiquitinating enzymes (DUBs) play a crucial role in reversing this process by removing ubiquitin from target proteins. Among them, USP2a has emerged as a promising target for cancer therapy due to its oncogenic properties in various cancer types, but its inhibitors have been limited. In this study, our aim was to optimize the structure of ML364, a USP2a inhibitor, and synthesize a series of its derivatives to develop potent USP2a inhibitors. Compound 8v emerged as a potential USP2a inhibitor with lower cytotoxicity compared to ML364. Cellular assays demonstrated that compound 8v effectively reduced the levels of USP2a substrates and attenuated cancer cell growth. We confirmed its direct interaction with the catalytic domain of USP2a and its selective inhibitory activity against USP2a over other USP subfamily proteins (USP7, 8, or 15). In conclusion, compound 8v has been identified as a potent USP2a inhibitor with substantial potential for cancer therapy. English Academic Press Structural optimization and biological evaluation of ML364 based derivatives as USP2a inhibitors Article 10.1016/j.bioorg.2024.107222 1 Bioorganic Chemistry, v.145 Bioorganic Chemistry 145 N scie scopus 001204401000001 Biochemistry & Molecular Biology Chemistry, Organic Biochemistry & Molecular Biology Chemistry Article UBIQUITIN CANCER ARREST CYCLIN D1 Inhibitor 4-(trifluoromethyl)benzamide scaffold Deubiquitinating enzymes USP2a