Cell cycle regulation and anticancer drug discovery

Abstract

Cellular growth, development, and differentiation are tightly controlled by a conserved biological mechanism: the cell cycle. This cycle is primarily regulated by cyclin-dependent kinase (CDK)-cyclin complexes, checkpoint kinases, and CDK inhibitors. Deregulation of the cell cycle is a hallmark of the transformation of normal cells into tumor cells. Given its importance in tumorigenesis, several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers-both as single-agent therapy and in combination with traditional cytotoxic or molecular targeting agents. In this review, we discuss the mechanisms underlying cell cycle regulation and present small-molecule anticancer drugs that are under development, including both pan-CDK inhibitors and CDK4/6-selective inhibitors. In addition, we provide an outline of some promising CDK inhibitors currently in preclinical and clinical trials that target cell cycle abnormalities in various cancers.

Keywords: CDK4/6-selective inhibitors; Cell cycle regulation; cyclin; cyclin-dependent kinases (CDK); pan-CDK inhibitors.

1

A schematic view of the cell cycle. Each phase in the cell cycle progression is regulated by cyclin-dependent kinases (CDKs) and their regulatory partner proteins, the cyclins, and CDK inhibitors.

2

The side effects and targets of cyclin-dependent kinase (CDK) inhibitors as anti-cancer drugs. Pan and CDK4/6-selective CDK inhibitors have different side effects and targets.