2. Academic Validation
  3. Optimization of Novel Quinazolines as Potent Aurora Kinase Inhibitors for Triple-Negative Breast Cancer Treatment

Optimization of Novel Quinazolines as Potent Aurora Kinase Inhibitors for Triple-Negative Breast Cancer Treatment

  • J Med Chem. 2025 Sep 11;68(17):18197-18215. doi: 10.1021/acs.jmedchem.5c00107.
Liang Long 1 2,  Bin Zhang 1,  Wei Peng 1,  Yujia Pan 3 4,  Hongjin Zhai 1,  Bao Cheng 1,  Zhengchao Tu 5,  Zijie Long 6,  Huihao Zhou 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, State Key Laboratory of Traditional Chinese Medicine Syndrome, 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.
  • 5 Jinan University College of Pharmacy, Guangzhou 510632, P. R. China.
  • 6 Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, P. R. China.
PMID: 40852972 DOI: 10.1021/acs.jmedchem.5c00107
Abstract

This work describes the discovery of a new series of Aurora Kinase inhibitors based on quinazoline skeleton derived from ENMD-2076, as well as the first X-ray cocrystal structure complexes of vinyl-quinazoline 9h with Aurora A. Replacing pyrimidine with quinazoline improved Anticancer activity and facilitated cocrystal formation. Compounds 9a and 9h showed excellent Aurora A kinase inhibition, with IC50 values of 6.0 and 2.8 nM, respectively. 9h demonstrated superior activity against TNBC MDA-MB-231 cells with an IC50 value of 48 nM and achieved 59% tumor growth inhibition in xenograft models, vs ENMD-2076's 33% with no observable toxicity. Mechanistic studies using immunoblotting, immunofluorescence staining, and flow cytometry showed that 9h outperforms ENMD-2076 in inhibiting Aurora A kinase activation, preventing spindle formation, arresting the cell cycle, and inducing cell Apoptosis. Thus, 9h has the potential for further optimization and is a promising Anticancer drug candidate.

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