Recent Advances in the Development of Selective Small Molecule Inhibitors for Cyclin-Dependent Kinases

Abstract

Loss of normal cell cycle regulation is the hallmark of human cancers, and alteration of the components involved in cell cycle regulation occurs in most human tumors. This suggests that Cyclin dependent kinases (CDKs) are an attractive target for the development of pharmacological agents for the treatment of cancer. Recently, CDK family members that are not directly involved in cell cycle regulation have been identified. This includes CDK7, CDK8, and CDK9, which participate in transcription regulation, and CDK5, which plays a role in neuronal and secretory functions. Given the involvement of CDKs in multiple cellular processes, development of selective small molecule inhibitors for specific CDKs is expected to help clarify whether improved specificity of cell cycle CDK inhibitors will enhance their therapeutic potential in cancer treatment. Selective inhibitors are also needed as tools to explore the biology of diseases in which CDKs may participate and to help develop therapeutics to treat them. Intensive screening and drug design based on CDK/inhibitor co-crystal structure and SAR studies have led to the identification of a large variety of chemical inhibitors of CDKs. Although they are competitive with ATP at the catalytic site, their kinase selectivity varies greatly, and inhibitors selective for certain CDKs have begun to be identified. There are currently two categories of selective CDK inhibitors: those that are selective for CDK2 and CDK1 and those that are selective for CDK4/6. These two types of inhibitors have different effects on tumor cells and are expected to be useful in the treatment of cancer.

Genetic Unmasking of an Epigenetically Silenced microRNA in Human Cancer Cells

“…Using computational prediction for miR-124a target genes, we observed that CDK6 was one of the best potential targets for miR-124a. CDK6 is involved in cell cycle progression and differentiation (17), and it constitutes an attractive target for the development of anticancer compounds (18). Using CDK6 Western blot analyses, we observed that whereas the original HCT-116 cells with miR-124a methylation-associated silencing strongly expressed CDK6, the cells treated with the demethylating agent or the DKO cells showed CDK6 down-regulation (Fig.…”

Cell Cycle Synchronization at the G2/M Phase Border by Reversible Inhibition of CDK1

“…9,10 All published CDK1 inhibitors are dual CDK1/CDK2, pan-CDK inhibitors, or their cell cycle profiles have been likely affected by off-target activities. 11 The recently published CDK1 inhibitor, RO-3306, appears to have sufficient selectivity to CDK1 vs. CDK2 (>10-fold) and shows an effective G 2 phase block consistent with specific inhibition of its molecular target in the cellular context. 12 Cell cycle analysis revealed that over 95% of the cycling cells from several human cancer cell lines were arrested in G 2 /M phase after treatment with 9 mM RO-3306.…”

Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1

“…This deficiency is due, in part, to the lack of specific molecular tools for reversible modulation of CDK1 activity in vivo. Several potent small-molecule inhibitors have been reported, but their activity and cell cycle profiles are not consistent with specific CDK1 inhibition (9,10). Here, we identify a selective and reversible inhibitor of the catalytic activity of human CDK1͞cyclin B1 and CDK1͞cyclin A complexes that allows synchronization of proliferating cells in the late G 2 phase and probing of CDK1 function in the cellular context.…”