Discovery of N-benzylbenzamide-based allosteric inhibitors of Aurora kinase A

• Published in: Bioorganic & medicinal chemistry Vol. 102; p. 117658
• Main Authors: Lee, Hyomin, Kim, Euijung, Hwang, Narae, Yoo, Jesik, Nam, Yunju, Hwang, Injeoung, Park, Jin-Gyeong, Park, Sang-Eun, Chung, Kyung-Sook, Won Chung, Hwan, Song, Chiman, Ji, Mi-Jung, Park, Hyun-Mee, Lee, In-Kyun, Lee, Kyung-Tae, Joo Roh, Eun, Hur, Wooyoung
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.03.2024; Elsevier
• Subjects: Allosteric inhibitor; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; AurkA; Aurora kinase; Aurora Kinase A; Biochemistry & Molecular Biology; Cell Cycle Proteins; Chemistry; Chemistry, Medicinal; Chemistry, Organic; DNA Replication; Humans; Life Sciences & Biomedicine; Neoplasms - drug therapy; Pharmacology & Pharmacy; Physical Sciences; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Science & Technology; TPX2; Y pocket; Allosteric inhibitor; TPX2; Aurora kinase; Y pocket; AurkA; ACTIVATION; MECHANISM; STRUCTURAL BASIS; SMALL-MOLECULE INHIBITORS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2024.117658

[Display omitted] •Novel AurkA allosteric inhibitors of N-benzylbenzamide backbone were designed and synthesized.•The most potent analogue 6h (AurkA IC50 = 6.50 μM) was comparable to the activity of AurkinA, the most potent AurkA allosteric inhibitor.•6h dissipated the interaction between AurkA and its activator TPX2 by binding to the Y-pocket of AurkA.•6h suppressed the DNA replication during G/S transition, which is a non-catalytic function of AurkA.•Docking analysis of 6h showed several crucial interactions with the residues in Y-pocket and was well-coherent with the structure–activity relationship. 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 μM) 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.