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  2. Discovery of novel pyrimidine-based benzothiazole derivatives as potent cyclin-dependent kinase 2 inhibitors with anticancer activity

Discovery of novel pyrimidine-based benzothiazole derivatives as potent cyclin-dependent kinase 2 inhibitors with anticancer activity

  • Eur J Med Chem. 2019 Oct 1:179:196-207. doi: 10.1016/j.ejmech.2019.06.055.
Peng-Cheng Diao 1 Wei-Yuan Lin 1 Xie-Er Jian 1 Yan-Hong Li 1 Wen-Wei You 2 Pei-Liang Zhao 3
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China.
  • 2 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China. Electronic address: youww@smu.edu.cn.
  • 3 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, PR China. Electronic address: plzhao@smu.edu.cn.
Abstract

To develop novel CDK2 inhibitors as Anticancer agents, a series of novel pyrimidine-based benzothiazole derivatives were designed and synthesized. Initial biological evaluation demonstrated some of target compounds displayed potent antitumor activity in vitro against five Cancer cell lines. Especially, the analogue 10s exhibited approximately potency with AZD5438 toward four cells including HeLa, HCT116, PC-3, and MDA-MB-231 with IC50 values of 0.45, 0.70, 0.92, 1.80 μM, respectively. More interestingly, the most highly active compound 10s in this study also possessed promising CDK2/cyclin A2 inhibitory activities with IC50 values of 15.4 nM, which was almost 3-fold potent than positive control AZD5438, and molecular docking studies revealed that the analogue bound efficiently with the CDK2 binding site. Further studies indicated that compound 10s could induce cell cycle arrest and Apoptosis in a concentration-dependent manner. These observations suggest that pyrimidine-benzothiazole hybrids represent a new class of CDK2 inhibitors and well worth further investigation aiming to generate potential Anticancer agents.

Keywords

Antiproliferative activity; Benzothiazole; CDK2 inhibitor; Pyrimidine.

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