Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs

Abstract

The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases (CDKs) is a hallmark of cancer. The inhibition of CDKs is a highly promising and attractive strategy for the development of anticancer drugs. In particular, third-generation CDK inhibitors can selectively inhibit CDK4/6 and regulate the cell cycle by suppressing the G1 to S phase transition, exhibiting a perfect balance between anticancer efficacy and general toxicity. To date, three selective CDK4/6 inhibitors have received approval from the U.S. Food and Drug Administration (FDA), and 15 CDK4/6 inhibitors are in clinical trials for the treatment of cancers. In this perspective, we discuss the crucial roles of CDK4/6 in regulating the cell cycle and cancer cells, analyze the rationale for selectively inhibiting CDK4/6 for cancer treatment, review the latest advances in highly selective CDK4/6 inhibitors with different chemical scaffolds, explain the mechanisms associated with CDK4/6 inhibitor resistance and describe solutions to overcome this issue, and briefly introduce proteolysis targeting chimera (PROTAC), a new and revolutionary technique used to degrade CDK4/6.

DNMT3A Mutation-Induced CDK1 Overexpression Promotes Leukemogenesis by Modulating the Interaction between EZH2 and DNMT3A

“…Further in vivo experiments are needed to validate our results. The CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib have been recently approved by the Food and Drug Administration (FDA) for the treatment of breast cancer [ 45 ]. A naturally derived small molecule CDK1 and AKT inhibitor terameprocol has shown safety and a partial response in some advanced leukemia patients [ 46 ].…”

CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal

“…This is supported by preliminary clinical data suggesting that these inhibitors may be beneficial for treating non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, mantle cell lymphoma, triple-negative breast cancer and acute myeloid leukaemia 10,13-17 . Currently, there are at least 18 different CDK4/6 inhibitors being tested in over 100 clinical trials against various tumour types (for reviews see: 2,11,12,18,19 ). The hope is that these targeted cell cycle inhibitors may be widely applicable for cancer treatment, perhaps offering an alternative to the non-targeted, and considerably more toxic, DNA damaging agents or microtubule poisons that are currently in widespread clinical use.…”

Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy

“…CDK2 inhibits the differentiation of myeloid cells by activating PRDX2, while inhibition of CDK2 drives differentiation in the five major subtypes of acute myelocytic leukemia (AML) 27 . CDK4/6-retinoblastoma (Rb) pathway regulates G1/S checkpoints in the cell cycle, and it's a general phenomenon that excessive activation in this pathway leads to booming cell proliferation in various cancers 28 . As for transcription related CDKs, CDK7 can drive oncogene transcriptional addiction, and inhibiting CDK7 leads to genome instability and activates antitumor immunity in cancer cells 29 , 30 .…”