Design, synthesis, and biological evaluation of a potent PLK4 inhibitor WY29 with 1H-pyrazolo[3,4-d]pyrimidine scaffold.
Lin WangYu SunJingkai WangYanli XueYin SunQiaohua QinYixiang SunDongmei ZhaoMaosheng ChengPublished in: Archiv der Pharmazie (2022)
Centriole duplication occurs once per cell cycle and is regulated by Polo-like kinase 4 (PLK4). Overexpression of PLK4 in somatic cells can lead to the excessive formation of centrioles, directly causing chromosome segregation errors and tumorigenesis. In this study, we described our efforts to develop a series of PLK4 inhibitors with 1H-pyrazolo[3,4-d]pyrimidine core, and further structure- and receptor-based design and optimization resulted in a potent inhibitor WY29 (IC 50 = 0.027 μM), which exhibited good selectivity to other PLK family members (PLK1-3). At the cellular level, compound WY29 showed excellent antiproliferative activity against three breast cancer cell lines (MCF-7, BT474, and MDA-MB-231) while weak inhibitory activity was found on normal cell line HUVECs. In addition, the in vitro preliminary drug-like properties evaluation of compound WY29 showed outstanding stability in human plasma and liver microsomes, and weak inhibitory activity against the major subtypes of human cytochrome P450. Also, the drug-like properties prediction of compound WY29 displayed remarkable drug-like properties (drug-likeness mode score: 1.06). In conclusion, these results support the further development of compound WY29 as a lead compound for PLK4-targeted anticancer drug discovery.
Keyphrases
- cell cycle
- drug discovery
- cell proliferation
- adverse drug
- breast cancer cells
- endothelial cells
- induced apoptosis
- cell cycle arrest
- emergency department
- drug induced
- transcription factor
- patient safety
- cell death
- physical activity
- anti inflammatory
- signaling pathway
- young adults
- cancer therapy
- protein kinase
- oxidative stress
- genome wide
- pi k akt
- tissue engineering