2. Academic Validation
  3. Discovery of N-benzylbenzamide-based allosteric inhibitors of Aurora kinase A

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

  • Bioorg Med Chem. 2024 Mar 15:102:117658. doi: 10.1016/j.bmc.2024.117658.
Hyomin Lee 1,  Euijung Kim 2,  Narae Hwang 3,  Jesik Yoo 4,  Yunju Nam 3,  Injeoung Hwang 5,  Jin-Gyeong Park 6,  Sang-Eun Park 7,  Kyung-Sook Chung 7,  Hwan Won Chung 8,  Chiman Song 9,  Mi-Jung Ji 10,  Hyun-Mee Park 10,  In-Kyun Lee 9,  Kyung-Tae Lee 7,  Eun Joo Roh 11,  Wooyoung Hur 12
Affiliations

Affiliations

  • 1 Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Biomedical Science and Technology, UST KIST School, Seoul 02792, Republic of Korea.
  • 2 Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Department of Chemistry, Korea University, Seoul 02841, Republic of Korea.
  • 3 Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
  • 4 Division of Biomedical Science and Technology, UST KIST School, Seoul 02792, Republic of Korea; Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
  • 5 Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; HY-KIST Bioconvergence, Hanyang University, Seoul 04763, Republic of Korea.
  • 6 Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Department of Biotechnology, Korea University, Seoul 02841, Republic of Korea.
  • 7 Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 8 Computational Science Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
  • 9 Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
  • 10 Advanced Analysis Data Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
  • 11 Division of Biomedical Science and Technology, UST KIST School, Seoul 02792, Republic of Korea; Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea. Electronic address: r8636@kist.re.kr.
  • 12 Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; HY-KIST Bioconvergence, Hanyang University, Seoul 04763, Republic of Korea. Electronic address: whur@kist.re.kr.
PMID: 38460487 DOI: 10.1016/j.bmc.2024.117658
Abstract

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.

Keywords

Allosteric inhibitor; AurkA; Aurora kinase; TPX2; Y pocket.

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