2. Academic Validation
  3. Discovery of a Potent and Highly Selective Inhibitor of Aurora A Kinase

Discovery of a Potent and Highly Selective Inhibitor of Aurora A Kinase

  • ACS Med Chem Lett. 2025 Sep 17;16(10):2057-2069. doi: 10.1021/acsmedchemlett.5c00480.
Liang Long 1 2,  Hongjin Zhai 1,  Bin Zhang 1,  Chengchen Zhu 1,  Xiaoyi Deng 1,  Albert S C Chan 1,  Quentin Liu 3 4,  Gui Lu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China.
  • 2 Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China.
  • 3 Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, P. R. China.
  • 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China.
PMID: 41089486 DOI: 10.1021/acsmedchemlett.5c00480
Abstract

Aurora Kinase A, a serine-threonine kinase frequently overexpressed in cancers, remains unaddressed by clinically approved inhibitors. Our previously endeavors unveiled a unique class of quinazolin-4-amine derivatives as potent, selective Aurora A kinase inhibitors. To further enhance therapeutic potential and Aurora A selectivity, we conducted systematic structural optimization and developed compound 5h, which exhibits potent antiproliferative activity across human Cancer cell linesparticularly in triple-negative breast Cancer MDA-MB-231 cells. Crucially, 5h exhibits 362-fold selectivity for Aurora A over Aurora B, a critical feature for therapeutic efficacy and safety. Molecular dynamics simulations reveal its selectivity arises from unique C-H/π interactions, enhanced hydrophobic contacts, an open Aurora A binding pocket, and tighter protein packing. At submicromolar concentrations, 5h effectively suppresses Aurora A autophosphorylation. Furthermore, it significantly inhibits tumor growth in MDA-MB-231 xenograft models, supporting its development as a promising Anticancer candidate.

Keywords

Aurora kinase A; anticancer drugs; kinase inhibitors; triple negative breast cancer.

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