2. Academic Validation
  3. Synthesis and SAR of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent and selective CDK4/6 inhibitors

Synthesis and SAR of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent and selective CDK4/6 inhibitors

  • Eur J Med Chem. 2018 Sep 5:157:935-945. doi: 10.1016/j.ejmech.2018.08.043.
Hui Zhao 1,  Xiaoxia Hu 1,  Kai Cao 1,  Yue Zhang 1,  Kuantao Zhao 1,  Chunlei Tang 2,  Bainian Feng 3
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China.
  • 2 School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China. Electronic address: tangcl@jiangnan.edu.cn.
  • 3 School of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China. Electronic address: fengbainian@jiangnan.edu.cn.
PMID: 30165341 DOI: 10.1016/j.ejmech.2018.08.043
Abstract

CDK4/6 pathway is an attractive target for development of anti-cancer drugs. Herein, we reported the design and synthesis of a series of 4,5-dihydro-1H-pyrazolo [4,3-h]quinazoline derivatives as selective CDK4/6 inhibitors. Applied with the optimizing strategy to the initial scaffold, it is found that compound 13n is able to selectively inhibit CDK4 and CDK6 with IC50 values 0.01 and 0.026 μM, respectively. The compound showed good anti-proliferative activity when tested in a panel of tumor cell lines with CDK4/6 related mechanism of action, the results clearly suggest that compound 13n works much better than Ly2385219 which is a selective CDK4/6 inhibitor. This compound was also found to have favorable pharmacokinetic parameters. Taken together, compound 13n could be selected for further preclinical evaluation.

Keywords

Anticancer; Cell cycle; Cyclin dependent kinase; Kinase selectivity.

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