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

Hui Zhao; Xiaoxia Hu; Kai Cao; Yue Zhang; Kuantao Zhao; Chunlei Tang; Bainian Feng

doi:10.1016/j.ejmech.2018.08.043

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. Epub 2018 Aug 18.

Authors

Hui Zhao¹, Xiaoxia Hu¹, Kai Cao¹, Yue Zhang¹, Kuantao Zhao¹, Chunlei Tang², Bainian Feng³

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
Cyclin-Dependent Kinase 4 / metabolism
Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
Cyclin-Dependent Kinase 6 / metabolism
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Male
Mice
Mice, Inbred ICR
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology*
Quinazolines / chemical synthesis
Quinazolines / chemistry*
Quinazolines / pharmacology*
Structure-Activity Relationship

Substances

4,5-dihydro-1H-pyrazolo(4,3-h)quinazoline
Antineoplastic Agents
Protein Kinase Inhibitors
Pyrazoles
Quinazolines
CDK4 protein, human
CDK6 protein, human
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6