A review on the role of cyclin dependent kinases in cancers

Abstract

The Cyclin-dependent kinase (CDK) class of serine/threonine kinases has crucial roles in the regulation of cell cycle transition and is mainly involved in the pathogenesis of cancers. The expression of CDKs is controlled by a complex regulatory network comprised of genetic and epigenetic mechanisms, which are dysregulated during the progression of cancer. The abnormal activation of CDKs results in uncontrolled cancer cell proliferation and the induction of cancer stem cell characteristics. The levels of CDKs can be utilized to predict the prognosis and treatment response of cancer patients, and further understanding of the function and underlying mechanisms of CDKs in human tumors would pave the way for future cancer therapies that effectively target CDKs. Defects in the regulation of cell cycle and mutations in the genes coding cell-cycle regulatory proteins lead to unrestrained proliferation of cells leading to formation of tumors. A number of treatment modalities have been designed to combat dysregulation of cell cycle through affecting expression or activity of CDKs. However, effective application of these methods in the clinical settings requires recognition of the role of CDKs in the progression of each type of cancer, their partners, their interactions with signaling pathways and the effects of suppression of these kinases on malignant features. Thus, we designed this literature search to summarize these findings at cellular level, as well as in vivo and clinical levels.

Quiescent Cancer Cells—A Potential Therapeutic Target to Overcome Tumor Resistance and Relapse

“…Modulating the expression levels of cyclin-dependent kinases also manipulates the cancer cell state. Cyclin-dependent kinases (CDKs) are a group of serine/threonine kinases that form complexes with cyclins to stabilize, activate, and phosphorylate their target genes, control cell cycle checkpoints and transcription, and regulate cellular proliferation [ 73 , 74 , 75 ]. Given their important roles in cell growth, the inhibition of cyclins and CDKs may be another possible approach to maintain QCC status and delay tumor recurrence.…”

Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers

“…To compound 22a (80 mg, 0.220 mmol) was added 4 M HCl in dioxane (2.mL, 0.220 mmol) at 0 °C and stirred at rt for 2 h. The reaction mixture was evaporated in vacuo, and the residue was dissolved in MeOH and passed through a PL-HCO3 MP SPE 200 mg/6 mL cartridge, eluting with MeOH to give compound 22 (26.03 mg,0.098 mmol, 43.97% yield) as a light-yellow gum. 1 (1S,3S)-N3-(5S-butylpyrazolo [1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diamine (27). To compound 27e (105 mg, 0.280 mmol; see Supporting Information for synthesis) was added 4 M HCl in dioxane (2 mL, 0.280 mmol), and the mixture was stirred at rt for 2 h. The reaction mixture was evaporated in vacuo, and the residue was dissolved in MeOH and passed through PL-HCO3 MP SPE 200 mg/6 mL cartridge, eluting with MeOH to give compound 27 (20.6 mg,0.075 mmol, 26.7% yield) as a light-yellow gum.…”

“…The reaction mixture was evaporated in vacuo, and the residue was dissolved in MeOH and passed through by PL-HCO3 MP SPE 200 mg/6 mL cartridge, eluting with MeOH, to give compound 8 (32.01 mg,0.125 mmol, 57.62% yield) as a light-yellow gum. 1…”

“…To compound 20a (80 mg, 0.220 mmol) was added 4 M HCl in dioxane (2.mL, 0.220 mmol) at 0 °C, and the mixture was stirred at rt for 2 h. The reaction mixture was evaporated in vacuo, and the residue was dissolved in MeOH and passed through a PL-HCO3 MP SPE 200 mg/6 mL cartridge, eluting with MeOH to give compound 20 (31.02 mg, 0.116 mmol, 52.14% yield) as a light-yellow gum. 1…”

Prognostic and immunological characteristics of CDK1 in lung adenocarcinoma: A systematic analysis

“…With the induction of cyclins, each CDK is activated alternately to drive the completion of the cell cycle in an orderly manner ( 7 ). There are 21 genes encoding CDKs and 5 genes encoding CDK-like (CDKL) kinases ( 8 ), and these proteins are involved in the regulation of transcription, epigenetic mechanisms, metabolic processes, and the self-renewal of stem cells ( 7 , 9 ). Due to their crucial role in cell proliferation, CDKs are considered natural targets for antitumor treatment ( 6 ).…”