Design, synthesis, and biological evaluation of novel pyrazolo [3,4-d]pyrimidine derivatives as potent PLK4 inhibitors for the treatment of TRIM37-amplified breast cancer

化学 激酶 嘧啶 铅化合物 IC50型 体内 癌症 癌细胞 生物化学 体外 药理学 生物 遗传学 生物技术
作者
Yin Sun,Yu Sun,Lin Wang,Tianxiao Wu,Wenbo Yin,Jingkai Wang,Yanli Xue,Qiaohua Qin,Yixiang Sun,Huali Yang,Dongmei Zhao,Maosheng Cheng
出处
期刊:European journal of medicinal chemistry [Elsevier]
卷期号:238: 114424-114424 被引量:10
标识
DOI:10.1016/j.ejmech.2022.114424
摘要

Serine/threonine-protein kinase polo-like kinase 4 (PLK4) is a mitosis-associated protein kinase that plays a vital role in the duplication of centrioles in dividing cells and is considered a promising target of synthetic lethality in TRIM37-amplified breast cancer. Herein, based on a rational drug design strategy, we described a series of pyrazolo [3,4-d]pyrimidine derivatives as potent PLK4 inhibitors and dissected the relevant structure-activity relationships (SARs). Most compounds showed potent suppressive activities against PLK4, with IC50 values of < 10 nM. Among them, compound 24j (PLK4 IC50 = 0.2 nM) displayed potent enzyme inhibition and good selectivity in a panel of 35 kinases. At the cellular level, compound 24j exhibited notable antiproliferative activities against MCF-7, BT474, and MDA-MB-231 cells, with IC50 values of 0.36, 1.35, and 2.88 μM, respectively. Compound 24j killed TRIM37-amplified breast cancer cells. Moreover, we evaluated the clone formation, proliferation, cycle arrest, and migration abilities of compound 24j using MCF-7 cells. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 24j showed remarkable plasma stability, moderate liver microsomal stability, and weak inhibitory activity against the main subtypes of human cytochrome P450. Based on in vivo pharmacokinetic studies in Sprague Dawley rats, compound 24j exhibited a relatively high plasma clearance and a low F value (8.03%). Overall, these results support the further development of compound 24j as a potential lead compound to treat TRIM37-amplified breast cancer.
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