Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action
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ABSTRACT:
SUBMITTER: Łukasik P
PROVIDER: S-EPMC8001317 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cyclin-dependent kinases (CDKs) are protein kinases characterized by needing a separate subunit - a cyclin - that provides domains essential for enzymatic activity. CDKs play important roles in the control of cell division and modulate transcription in response to several extra- and intracellular cues. The evolutionary expansion of the CDK family in mammals led to the division of CDKs into three cell-cycle-related subfamilies (Cdk1, Cdk4 and Cdk5) and five transcriptional subfamilies (Cdk7, Cdk8, Cdk9, Cdk11 and Cdk20). Unlike the prototypical Cdc28 kinase of budding yeast, most of these CDKs bind one or a few cyclins, consistent with functional specialization during evolution. This review summarizes how, although CDKs are traditionally separated into cell-cycle or transcriptional CDKs, these activities are frequently combined in many family members. Not surprisingly, deregulation of this family of proteins is a hallmark of several diseases, including cancer, and drug-targeted inhibition of specific members has generated very encouraging results in clinical trials.
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Project description:Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that act as key regulatory elements in cell cycle progression. We describe the development of highly potent diaminothiazole inhibitors of CDK2 (IC50 = 0.0009-0.0015 μM) from a single hit compound with weak inhibitory activity (IC50 = 15 μM), discovered by high-throughput screening. Structure-based design was performed using 35 cocrystal structures of CDK2 liganded with distinct analogues of the parent compound. The profiling of compound 51 against a panel of 339 kinases revealed high selectivity for CDKs, with preference for CDK2 and CDK5 over CDK9, CDK1, CDK4, and CDK6. Compound 51 inhibited the proliferation of 13 out of 15 cancer cell lines with IC50 values between 0.27 and 6.9 μM, which correlated with the complete suppression of retinoblastoma phosphorylation and the onset of apoptosis. Combined, the results demonstrate the potential of this new inhibitors series for further development into CDK-specific chemical probes or therapeutics.
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Project description:Cyclin-dependent kinases (CDK/Cyclins) form a family of heterodimeric kinases that play central roles in regulation of cell cycle progression, transcription and other major biological processes including neuronal differentiation and metabolism. Constitutive or deregulated hyperactivity of these kinases due to amplification, overexpression or mutation of cyclins or CDK, contributes to proliferation of cancer cells, and aberrant activity of these kinases has been reported in a wide variety of human cancers. These kinases therefore constitute biomarkers of proliferation and attractive pharmacological targets for development of anticancer therapeutics. The structural features of several of these kinases have been elucidated and their molecular mechanisms of regulation characterized in depth, providing clues for development of drugs and inhibitors to disrupt their function. However, like most other kinases, they constitute a challenging class of therapeutic targets due to their highly conserved structural features and ATP-binding pocket. Notwithstanding, several classes of inhibitors have been discovered from natural sources, and small molecule derivatives have been synthesized through rational, structure-guided approaches or identified in high throughput screens. The larger part of these inhibitors target ATP pockets, but a growing number of peptides targeting protein/protein interfaces are being proposed, and a small number of compounds targeting allosteric sites have been reported.
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Project description:Several cyclin-dependent kinases (CDKs) are known to have roles in transcriptional regulation. The datasets presented here are ChIP-seq experiments for different CDKs and RNA polymerase II in murine embryonic stem cells and Jurkat cells. ChIP-Seq of cyclin-dependent kinases in mouse embryonic stem cells and Jurkat human T cell acute lymphoblastic leukemia cell line
2014-08-03 | E-GEOD-60027 | biostudies-arrayexpress
Project description:Several cyclin-dependent kinases (CDKs) are known to have roles in transcriptional regulation. The datasets presented here are ChIP-seq experiments for different CDKs and RNA polymerase II in murine embryonic stem cells and Jurkat cells.
2014-08-03 | GSE60027 | GEO
Project description:With the significant increase in the availability of microbial genome sequences in recent years, resistance gene-guided genome mining has emerged as a powerful approach for identifying natural products with specific bioactivities. Here, we present the use of this approach to reveal the roseopurpurins as potent inhibitors of cyclin-dependent kinases (CDKs), a class of cell cycle regulators implicated in multiple cancers. We identified a biosynthetic gene cluster (BGC) with a putative resistance gene with homology to human CDK2. Using targeted gene disruption and transcription factor overexpression in Aspergillus uvarum, and heterologous expression of the BGC in Aspergillus nidulans, we demonstrated that roseopurpurin C (1) is produced by this cluster and characterized its biosynthesis. We determined the potency, specificity, and mechanism of action of 1 as well as multiple intermediates and shunt products produced from the BGC. We show that 1 inhibits human CDK2 with a Kiapp of 44 nM, demonstrates selectivity for clinically relevant members of the CDK family, and induces G1 cell cycle arrest in HCT116 cells. Structural analysis of 1 complexed with CDK2 revealed the molecular basis of ATP-competitive inhibition.
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Project description:Extensive studies in the past 30 years have established that cyclin-dependent kinases (CDKs) exert many diverse, important functions in a number of molecular and cellular processes that are at play during development. Not surprisingly, mutations affecting CDKs or their activating cyclin subunits have been involved in a variety of rare human developmental disorders. These recent findings are reviewed herein, giving a particular attention to the discovered mutations and their demonstrated or hypothesized functional consequences, which can account for pathological human phenotypes. The review highlights novel, important CDK or cyclin functions that were unveiled by their association with human disorders, and it discusses the shortcomings of mouse models to reveal some of these functions. It explains how human genetics can be used in combination with proteome-scale interaction databases to loom regulatory networks around CDKs and cyclins. Finally, it advocates the use of these networks to profile pathogenic CDK or cyclin variants, in order to gain knowledge on protein function and on pathogenic mechanisms.
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Project description:The fact that many cancer types display transcriptional addiction driven by dysregulation of oncogenic enhancers and transcription factors has led to increased interest in a group of protein kinases, known as transcriptional cyclin dependent kinases (tCDKs), as potential therapeutic targets. Despite early reservations about targeting a process that is essential to healthy cell types, there is now evidence that targeting tCDKs could provide enough therapeutic window to be effective in the clinic. Here, we discuss recent developments in this field, with an emphasis on highly-selective inhibitors and the challenges to be addressed before these inhibitors could be used for therapeutic purposes. Abbreviations: CAK: CDK-activating kinase;CDK: cyclin-dependent kinase;CMGC group: CDK-, MAPK-, GSK3-, and CLK-like;CTD: C-terminal repeat domain of the RPB1 subunit of RNA polymerase II;DRB: 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole;mCRPC: metastatic castration-resistant prostate cancer;NSCLC: non-small cell lung cancer;P-TEFb: positive elongation factor b;RNAPII: RNA polymerase II;S2: serine-2 of CTD repeats;S5: serine-5 of CTD repeats;S7: serine-7 of CTD repeats;SEC: super elongation complex;tCDK: transcriptional cyclin-dependent kinase;TNBC: triple-negative breast cancer.
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