Transcriptional CDKs
Transcriptional CDKs include CDK7, CDK8 and CDK9 and regulate the production of RNA from DNA; different family members are involved at different stages of transcription. Transcriptional CDKs, like other CDKs, are regulated by binding cyclins, although these cyclins do not fluctuate in expression levels in a cell cycle-dependent manner.
Transcriptional CDK Inhibitors |
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|---|---|
| Cat. No. | Product Name / Activity |
| 6438 | BRD 6989 |
| Cdk8 inhibitor; enhances IL-10 production | |
| 5608 | BS 181 dihydrochloride |
| Selective cdk7 inhibitor | |
| 7372 | CDK8/19i |
| Potent and selective CDK8 and CDK19 inhibitor; maintains pluripotency of mouse PSCs in culture | |
| 6535 | NVP 2 |
| Potent and selective ATP-competitive CDK9 inhibitor | |
| 4875 | Senexin A |
| Cdk8 inhibitor | |
| 7157 | YKL 5-124 |
| Potent and selective CDK7 inhibitor; induces cell cycle arrest | |
Degraders |
|
| Cat. No. | Product Name / Activity |
| 7528 | BSJ-4-116 |
| Selective CDK12 PROTAC® Degrader | |
| 7525 | dCeMM2 |
| Molecular glue Degrader; induces ubiquitination and degradation of cyclin K | |
| 7304 | JH-XI-10-02 |
| CDK8 Degrader (PROTAC®) | |
| 7813 | LL-K9-3 |
| Selective HyT-based degrader of the CDK9-cyclin T1 complex | |
| 7551 | NCT 02 |
| Induces degradation of CCNK and CDK12; molecular glue | |
| 6532 | THAL SNS 032 |
| Potent and selective Cdk9 Degrader | |
As well as regulating progression through the cell cycle, some cyclin-dependent kinases (CDKs) play a key role in controlling transcription of DNA to produce an RNA template. While some CDKs are involved in both processes, such as CDK1 and CDK2, several CDKs only function in control of transcription and are called Transcriptional CDKs. This group includes CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13 and CDK20. Cyclins that regulate transcriptional CDKs do not fluctuate in expression levels through the phases of the cell cycle like other cyclins, but regulate transcriptional CDKs through protein-protein interactions.
CDK7
CDK7 lacks the regulatory threonine residues in the n-terminal lobe found in other CDKs leading constitutive kinase activity of CDK7. CDK7 is a subunit of the 10-protein transcription factorTFIIH and phosphorylates RNA polymerase II (RNAPII) during initiation of transcription and promoter clearance. CDK7 also functions as a CDK-activating kinase (CAK), as it can phosphorylate other CDKs such as CDK1. Inhibition of CDK7 disrupts the activation of CDK1/cyclin B complexes and causes cell cycle arrest.
CDK8 and CDK19
CDK8 and CDK19 are highly related and bind cyclin C as part of the Mediator complex, a multi-protein complex that forms a bridge linking gene-specific activators to general RNAPII transcription machinery. CDK8/cyclin C phosphorylates several transcription factors, causing either transcriptional repression or activation, and is linked to p53 signaling, Wnt/β-catenin pathways, thyroid hormone signaling, and pathways downstream of receptor serine/threonine kinases (RSTKs), which are governed by SMAD signaling.
CDK8/19i (Cat. No. 7372) is a potent dual CDK8 and CDK19 inhibitor, with IC50 values of 2.9 and 14.1 nM respectively. Due to the interaction of CDK8/19 with signaling pathways that are associated with stem cell differentiation, this compound can be used to maintain pluripotency of mouse pluripotent stem cells (PSCs) in culture.
Figure 1: Structure of CDK8 (green) in complex with Cyclin C (orange). Taken from Schneider et al (2011) The Structure of CDK8/CycC Implicates Specificity in the CDK/Cyclin Family and Reveals Interaction with a Deep Pocket Binder. J.Mol.Biol. 412, 251. PMID: 21806996
Other Transcriptional CDKs
CDK9 is a component of TAK/P-TEFb complex that is an elongation factor for RNAPII-directed transcription. This CDK is activated by binding to cyclin T or K and phosphorylates the C-terminal domain of the largest subunit of RNAPII. CDK9 has been linked to HIV infection as HIV Tat protein interacts with both CDK9 and cyclin T.
LDC 000067 (Cat. No. 6752) is a potent CDK9 inhibitor that inhibits P-TEFb-dependent transcription and induced apoptosis in vitro. THAL SNS 032 (Cat. No. 6532) is a potent CDK9 Degrader, which induces selective, cereblon-dependent degradation of CDK9 in vitro and inhibits proliferation of leukemia cell lines.
Figure 2: Structure of CDK9 (green) in complex with cyclin T (orange). Taken from Baumali et al (2012) The CDK9 C-helix Exhibits Conformational Plasticity That May Explain the Selectivity of CAN508. ACS Chem Biol. 7, 811. PMID: 22292676
CDK10 and CDK11 control transcription by phosphorylation of transcription factors, hormone receptors and splicing factors. CDK10 is activated by cyclin M and phosphorylates transcription factor ETS2 to promote its degradation by the proteasome. CDK11 binds cyclin L and is involved in co-ordination between transcription and RNA processing, particularly alternative splicing of mRNA. CDK11 is also involved in the cell cycle; specifically its short form, which is expressed in G2/M phase and is required for the duplication of centrioles, correct spindle dynamics and chromatid cohesion at centromeres during mitosis.
CDK12 binds cyclin K and mainly controls transcription of long and complex genes and is specifically required for transcription of genes involved in DNA damage response via the homologous repair pathway. Both CDK12 and CDK13 are involved in forming transcripts of developing RNA.
CDK20 is activated by cyclin H and has been linked to stimulation of cell cycle progression by β-catenin. CDK20 also modulates activity of CDK2 and is an activating kinase of MAK-related kinase and intestinal cell kinase. Inhibition of CDK20 prevents entry into the cell cycle.