Design, synthesis, and biological evaluation of novel pyrimidin-2-amine derivatives as potent PLK4 inhibitors

Yanli Xue; Shuyi Mu; Pengkun Sun; Yin Sun; Nian Liu; Yu Sun; Lin Wang; Dongmei Zhao; Maosheng Cheng

doi:10.1039/d3md00267e

Design, synthesis, and biological evaluation of novel pyrimidin-2-amine derivatives as potent PLK4 inhibitors

RSC Med Chem. 2023 Jul 20;14(9):1787-1802. doi: 10.1039/d3md00267e. eCollection 2023 Sep 19.

Authors

Yanli Xue¹, Shuyi Mu¹, Pengkun Sun¹, Yin Sun¹, Nian Liu¹, Yu Sun¹, Lin Wang¹, Dongmei Zhao¹, Maosheng Cheng¹

Affiliation

¹ Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District 110016 Shenyang China medchemzhao@163.com.

PMID: 37731702
PMCID: PMC10507801 (available on 2024-07-20)
DOI: 10.1039/d3md00267e

Abstract

Serine/threonine protein kinase PLK4 is a master regulator of centriole duplication, which is significant for maintaining genome integrity. Accordingly, due to the detection of PLK4 overexpression in a variety of cancers, PLK4 has been identified as a candidate anticancer target. Thus, it is a very meaningful to find effective and safe PLK4 inhibitors for the treatment of cancer. However, the reported PLK4 inhibitors are scarce and have potential safety issues. In this study, a series of novel and potent PLK4 inhibitors with an aminopyrimidine core was obtained utilizing the scaffold hopping strategy. The in vitro enzyme activity results showed that compound 8h (PLK4 IC₅₀ = 0.0067 μM) displayed high PLK4 inhibitory activity. In addition, compound 8h exhibited a good plasma stability (t_1/2 > 289.1 min), liver microsomal stability (t_1/2 > 145 min), and low risk of DDIs. At the cellular level, it presented excellent antiproliferative activity against breast cancer cells. Taken together, these results suggest that compound 8h has potential value in the further research of PLK4-targeted anticancer drugs.