Optimization of Novel Quinazolines as Potent Aurora Kinase Inhibitors for Triple-Negative Breast Cancer Treatment
This work describes the discovery of a new series of Aurora kinase inhibitors based on quinazoline skeleton derived from <b>ENMD-2076</b>, as well as the first X-ray cocrystal structure complexes of vinyl-quinazoline <b>9h</b> with Aurora A. Replacing pyrimidine with quinazoline improved anticancer activity and facilitated cocrystal formation. Compounds <b>9a</b> and <b>9h</b> showed excellent Aurora A kinase inhibition, with IC<sub>50</sub> values of 6.0 and 2.8 nM, respectively. <b>9h</b> demonstrated superior activity against TNBC MDA-MB-231 cells with an IC<sub>50</sub> value of 48 nM and achieved 59% tumor growth inhibition in xenograft models, vs <b>ENMD-2076</b>'s 33% with no observable toxicity. Mechanistic studies using immunoblotting, immunofluorescence staining, and flow cytometry showed that <b>9h</b> outperforms <b>ENMD-2076</b> in inhibiting Aurora A kinase activation, preventing spindle formation, arresting the cell cycle, and inducing cell apoptosis. Thus, <b>9h</b> has the potential for further optimization and is a promising anticancer drug candidate.
Authors
- Bao Cheng (ORCID: https://orcid.org/0000-0001-7984-5812)
- Huihao Zhou (ORCID: https://orcid.org/0000-0002-9675-5007)
- Quentin Liu
- Zi‐Jie Long (ORCID: https://orcid.org/0000-0002-1616-6019)
- Yujia Pan (ORCID: https://orcid.org/0000-0002-4658-8650)
- Gui Lu (ORCID: https://orcid.org/0000-0003-0089-0907)
- Wei Peng (ORCID: https://orcid.org/0000-0002-5636-9849)
- Hongjin Zhai
- Zhengchao Tu (ORCID: https://orcid.org/0009-0000-1746-8687)
- Bin Zhang (ORCID: https://orcid.org/0000-0001-6922-9346)
- Long Liang (ORCID: https://orcid.org/0009-0003-1923-6187)
Institutions
- Guangzhou University of Chinese Medicine (CN)
- Sun Yat-sen University (CN)
- Jinan University (CN)
- Dalian Medical University (CN)
- State Administration of Traditional Chinese Medicine of the People's Republic of China (CN)
- Jinan University (LB)
- Sun Yat-sen University Cancer Center (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- State Key Laboratory of Oncology in South China
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-25
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00107
- Citations
- 2
- Primary Topic
- Microtubule and mitosis dynamics
- Type
- article
- Field-Weighted Citation Impact
- 2.30
Funders
- National Natural Science Foundation of China
- Guangdong Provincial Key Laboratory of Construction Foundation
- Basic and Applied Basic Research Foundation of Guangdong Province