Lee, Hyomin Kim, Euijung Hwang, Narae Yoo, Jesik Nam, Yunju Hwang, Injeoung Park, Jin-Gyeong Park, Sang-Eun Chung, Kyung-Sook Chung, Hwan Won Song, Chiman Ji, Mi-Jung Park, Hyun-Mee Lee, In-Kyun Lee, Kyung-Tae Roh, Eun Joo Hur, Wooyoung 2024-05-09T09:00:13Z 2024-05-09T09:00:13Z 2024-05-09 2024-03 0968-0896 https://pubs.kist.re.kr/handle/201004/149802 Aurora kinases (AurkA/B/C) regulate the assembly of bipolar mitotic spindles and the fidelity of chromosome segregation during mitosis, and are attractive therapeutic targets for cancers. Numerous ATP-competitive AurkA inhibitors have been developed as potential anti-cancer agents. Recently, a few allosteric inhibitors have been reported that bind to the allosteric Y-pocket within AurkA kinase domain and disrupt the interaction between AurkA and its activator TPX2. Herein we report a novel allosteric AurkA inhibitor (6h) of N-benzylbenzamide backbone. Compound 6h suppressed the both catalytic activity and non-catalytic functions of AurkA. The inhibitory activity of 6h against AurkA (IC50 = 6.50 mu M) was comparable to that of the most potent allosteric AurkA inhibitor AurkinA. Docking analysis against the Y-pocket revealed important pharmacophores and interactions that were coherent with structure-activity relationship. In addition, 6h suppressed DNA replication in G1-S phase, which is a feature of allosteric inhibition of AurA. Our current study may provide a useful insight in designing potent allosteric AurkA inhibitors. English Pergamon Press Ltd. Discovery of N-benzylbenzamide-based allosteric inhibitors of Aurora kinase A Article 10.1016/j.bmc.2024.117658 1 Bioorganic & Medicinal Chemistry, v.102 Bioorganic & Medicinal Chemistry 102 N scie scopus 001209089900001 2-s2.0-85186968196 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article SMALL-MOLECULE INHIBITORS STRUCTURAL BASIS ACTIVATION MECHANISM Aurora kinase AurkA Allosteric inhibitor Y pocket TPX2