Discovery of novel and selective CDK4/6 inhibitors by pharmacophore and structure-based virtual screening

Kai Yuan; Wenjian Min; Xiao Wang; Jiaxing Li; Wenbin Kuang; Fang Zhang; Shengnan Xie; Peng Yang

doi:10.4155/fmc-2020-0011

Discovery of novel and selective CDK4/6 inhibitors by pharmacophore and structure-based virtual screening

Future Med Chem. 2020 Jun;12(12):1121-1136. doi: 10.4155/fmc-2020-0011. Epub 2020 May 13.

Authors

Kai Yuan^{1

2}, Wenjian Min^{1

2}, Xiao Wang^{1

2}, Jiaxing Li^{1

2}, Wenbin Kuang^{1

2}, Fang Zhang^{1

2}, Shengnan Xie^{1

2}, Peng Yang^{1

2}

Affiliations

¹ State Key Laboratory of Natural Medicines & Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
² Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.

PMID: 32400188
DOI: 10.4155/fmc-2020-0011

Abstract

Aim: CDK4 and 6 are the key initiators in the transition from G1 to S phase in the cell cycle; thus, inhibition of CDK4/6 is a promising strategy for cancer treatment. Materials & methods: The Specs database and an in-house library were screened via the pharmacophore model and LibDock protocol and then the retrieved hits were clustered into 100 clusters. The CDK4/6 inhibitory activity of selected compounds was evaluated by CDK enzymatic assays, followed by chemical optimization of the top hit compound. Results & conclusion: The integration of pharmacophores and molecular docking offered us an effective method to discover the novel CDK4/6 inhibitor 10 and further chemical optimization led to the highly selective and potent CDK4/6 inhibitor 18, which exhibited potential for the treatment of multiple myeloma.

Keywords: CDK4/6 inhibitors; hit identification; molecular docking; multiple myeloma; pharmacophore.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
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
Drug Discovery*
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
Humans
Models, Molecular
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
CDK4 protein, human
CDK6 protein, human
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6