Targeting Protein-Protein Interactions to Inhibit Cyclin-Dependent Kinases

Author:

Klein Mark12

Affiliation:

1. Hematology/Oncology Section, Primary Care Service Line, Minneapolis VA Healthcare System, Minneapolis, MN 55417, USA

2. Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA

Abstract

Cyclin-dependent kinases (CDKs) play diverse and critical roles in normal cells and may be exploited as targets in cancer therapeutic strategies. CDK4 inhibitors are currently approved for treatment in advanced breast cancer. This success has led to continued pursuit of targeting other CDKs. One challenge has been in the development of inhibitors that are highly selective for individual CDKs as the ATP-binding site is highly conserved across this family of proteins. Protein-protein interactions (PPI) tend to have less conservation amongst different proteins, even within protein families, making targeting PPI an attractive approach to improving drug selectivity. However, PPI can be challenging to target due to structural and physicochemical features of these interactions. A review of the literature specific to studies focused on targeting PPI involving CDKs 2, 4, 5, and 9 was conducted and is presented here. Promising lead molecules to target select CDKs have been discovered. None of the lead molecules discovered have led to FDA approval; however, the studies covered in this review lay the foundation for further discovery and develop of PPI inhibitors for CDKs.

Funder

Department of Veterans Affairs, Office of Research and Development

Publisher

MDPI AG

Subject

Drug Discovery,Pharmaceutical Science,Molecular Medicine

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