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
  • 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: [email protected].
  • 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: [email protected].
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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