Cyclin-dependent Kinase (CDK) are serine-threonine kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. CDKs are relatively small proteins, with molecular weights ranging from 34 to 40 kDa, and contain little more than the kinase domain. In fact, yeast cells can proliferate normally when their CDK gene has been replaced with the homologous human gene. By definition, a CDK binds a regulatory protein called a cyclin. Without cyclin, CDK has little kinase activity; only the cyclin-CDK complex is an active kinase.
There are around 20 Cyclin-dependent kinases (CDK1-20) known till date. CDK1, 4 and 5 are involved in cell cycle, and CDK 7, 8, 9 and 11 are associated with transcription.
CDK levels remain relatively constant throughout the cell cycle and most regulation is post-translational. Most knowledge of CDK structure and function is based on CDKs of S. pombe (Cdc2), S. cerevisia (CDC28), and vertebrates (CDC2 and CDK2). The four major mechanisms of CDK regulation are cyclin binding, CAK phosphorylation, regulatory inhibitory phosphorylation, and binding of CDK inhibitory subunits (CKIs).
1.Liu N, et al. (2009) Recent research in selective cyclin-dependent kinase 4 inhibitors for anti-cancer treatment. Curr Med Chem. 16(36):4869-88.
2.Krystof V, et al. (2010) Cyclin-dependent kinase inhibitors as anticancer drugs. Curr Drug 2.Targets. 11(3):291-302.
3.Parry D, et al. (2010) Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 9(8):2344-53.
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Alsteropaullone (9-Nitropaullone, NSC 705701) is a derivative of kenpaullone, ATP-competitive inhibitor of CDKs and GSK3β, inhibits Cdk1/cyclin B, Cdk2/cyclin A, Cdk2/cyclin E and Cdk5/p25 with IC50 of 35, 15, 200 and 40 nM; exhibits specific antitumor activity against Group 3 medulloblastomas, causes inhibition of cell cycle-related genes, and down-regulation of MYC; inhibits the cytosolic degradation of β-catenin to alter the canonical Wnt signaling pathway in primary axis patterning, reduces tau phosphorylation.
THZ-1 hydrochloride is a potent, selective, covalent CDK7 inhibitor with IC50 of 3.2 nM; also weakly inhibits CDK12 with IC50 of 250 nM; displays broad-based activity a subset of cancer cell lines with IC50s of <200 nM; causes decreased cellular proliferation and an increase in apoptotic index (MCL-1, XIAP), disproportionally affects transcription of RUNX1 in Jurkat T-ALL cells; demonstrates efficacy against primary leukemia cells and in a bioluminescent xenografted model at 10mg/kg.
A novel, potent and selective inhibitor of CDK4/6 with biochemical IC50 of 1 nM and 4 nM for CDK4/cyclin D1 and CDK6/cyclin D3, respectively; displays >30-fold selectivity for CDK4/cyclin D1 over CDK2/cyclin A, CDK2/cyclin E, CDK5/p25, CDK5/p35, and CDK7/cyclin H/Mat1, 50-fold over CDK9/cyclin T; reversibly pauses the cell cycle in the G1 phase in CDK4/6-dependent cell lines, protects CDK4/6-dependent cells from chemotherapy-induced damage in vitro; induces a reversible cell-cycle arrest in murine and canine HSPCs; attenuates chemotherapy-induced myelosuppression in vivo.
MSC-2530818 (MSC 2530818, MSC2530818) is a potent, selective, and orally bioavailable CDK8 inhibitor with IC50 of 2.6 nM; binds to CDK8 and CDK19 with similar affinity (4 nM), and displays good selectivity profile in a 264 kinase panel with exception of GSK3α (IC50=691 nM); potently inhibits of phospho-STAT1 S727 in SW620 cells (IC50=8 nM), shows potent inhibition of WNT-dependent transcription in human cancer cell lines; demonstrates tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model.
A novel specific, effective p18 (p18INK4C) inhibitor that can selectively promote HSCs expansion with EC50 of 5.21 nM; inhibits p18, and then activates CDK4/6, promotes HSCs expansion in both murine and human models; shows no activity in promoting the proliferation of leukemia cells, and no significant cytotoxicity toward 32D cells or HSCs.
THZ 531 (THZ531) is a first-in-class, selective CDK12 and CDK13 covalent inhibitor with IC50 of 158 nM and 69 nM, respectively; dispalys 50-fold selectivity over CDK7 and CDK9 (IC50 of 8.5 and 10.5 uM, respectively), and shows no appreciable inhibitory effect on ERK1; irreversiblely inhibits Jurkat cell proliferation with an IC50 of 50 nM, induces apoptosis in a dose- and time-dependent manner with low doses (<350 nM); selectively reduced Ser2 phosphorylation levels without appreciable effect on CTD pSer5/pSer7 levels, causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II, inhibits DDR and transcription factor gene expression.
CCT251545 is a potent, orally bioavailable inhibitor of Wnt signaling with IC50 of 5 nM, also is a potent and selective chemical probe for CDK8 and CDK19 with >100-fold selectivity over 291 other kinases; potently inhibits reporter-based readouts of basal WNT pathway activity in LS174T and SW480 cells in the absence of WNT ligand with IC50 of 23 and 190 nM, respectively; demonstrates potent inhibition of WNT pathway activity in APC mutant human colorectal cancer cell line with IC50 of 35 nM; inhibits phospho-STAT1SER727 levels in SW620 cells with IC50 of 9 nM; demonstrate in vivo activity in WNT-dependent tumors.
A potent and selective CDC7 inhibitor with IC50 of 3.3 nM.
LY2857785 is a potenrt, reversible and ATP-competitive CDK9 inhibitor with IC50 of 11 nM, also inhibits CDK8 (IC50=16 nM) and weakly inhibits CSK7 (IC50=246 nM); showes good selectivity against a panel of 114 protein kinases; inhibits RNAP II C-terminal domain (CTD) P-Ser2 and CTD P-Ser5 in U2OS cells with IC50 of 89 and 42 nM, dramatically decreases MCL1 protein levels to result in apoptosis in a variety of leukemia and solid tumor cell lines (MV-4-11 cell IC50=40 nM); inhibits RNAP II CTD P-Ser2 in vivo, demonstrates potent antitumor growth efficacy in tumor xenografts.
An ATP-competitive inhibitor of CDK1 and CDK2 with Ki of 5 uM and 12 uM respectively; inhibits human tumor cells with a mean GI50 of 13±7 uM; reduces CDK2-mediated phosphorylation of pRb, E2F transcriptional activity and proliferatio in both anti-estrogen-sensitive and resistant cells; also inhibits DNA topoisomerase II ATPase activity (IC50=300 uM).
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