A novel amino-pyrimidine inhibitor suppresses tumor growth via microtubule destabilization and Bmi-1 down-regulation
- Biochem Pharmacol. 2025 Mar:233:116783. doi: 10.1016/j.bcp.2025.116783.
- 1. Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Anti-tumor Molecular Target Technology Innovation Center, College of Life Science, Hebei Normal University, Shijiazhuang, China.
- 2. Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
- 3. Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Kyiv 02094 Ukraine.
- 4. Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY, United States; Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, United States.
- 5. Department of Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou, China.
- 6. Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Anti-tumor Molecular Target Technology Innovation Center, College of Life Science, Hebei Normal University, Shijiazhuang, China. Electronic address: [email protected].
- 7. Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Anti-tumor Molecular Target Technology Innovation Center, College of Life Science, Hebei Normal University, Shijiazhuang, China. Electronic address: [email protected].
Colorectal Cancer (CRC), one of the diseases posing a threat to global health, according to the latest data, is the third most common Cancer globally and the second leading cause of cancer-related deaths. The development and refinement of novel structures of small molecular compounds play a crucial role in tumor treatment and overcoming drug resistance. In this study, our objective was to screen and characterize novel compounds for overcoming drug resistance via the B Lymphoma Mo-MLV insertion region 1 (Bmi-1) reporter screen assay. The stable cell line harboring the Bmi-1 reporter gene was utilized to screen 300 compounds, leading to the identification of an amino-pyrimidine compound, APD-94. In vitro, APD-94 markedly inhibited Cancer cell proliferation and decreased Bmi-1 expression at both the RNA and protein levels. In vivo, APD-94 repressed the growth of HT29 cell xenografts in NOD/SCID mice without notable side effects. Flow cytometry results demonstrated that APD-94 induced G2/M phase arrest and Apoptosis in cells. APD-94 was identified as a novel inhibitor of microtubule polymerization by directly targeting the tubulin. Furthermore, APD-94 was more effective in overcoming the resistance to paclitaxel in paclitaxel-resistant A549/Tax cells. This bifunctional inhibitor is a promising candidate drug for CRC treatment.