In Part 1, we reviewed the fundamentals of transcription and the CDK family. In this article, we focus on CDK7 and CDK8, two kinases that act at the transcriptional “starting line.” While both regulate initiation, their roles and drug discovery prospects differ considerably.
1. Transcription initiation — events at the promoter
Transcription begins with RNA polymerase II recruitment to promoters, together with general transcription factors. CDK7, part of the TFIIH complex, plays a central role in triggering initiation by phosphorylating Pol II CTD at Ser5.
1-1. Role of CDK7
- Phosphorylates Pol II CTD Ser5, essential for initiation.
- Acts as CAK (CDK-activating kinase), activating CDKs 1/2/4/6.
Thus, CDK7 functions as both a transcriptional and cell cycle regulator.
1-2. Role of CDK8
- Component of the Mediator kinase module, modulating transcriptional output.
- Functions as a “volume control” for gene expression rather than an on/off switch.
- Linked to super-enhancer regulation of oncogenic transcription in cancers.
2. CDK7 — molecular mechanisms and disease relevance
CDK7 serves as the “flag bearer” of transcription initiation. Ser5 phosphorylation signals Pol II to start RNA synthesis. Additionally, CDK7 activates other CDKs, linking transcription and the cell cycle.
2-1. Disease associations
- Breast cancer: supports hormone receptor-dependent transcription.
- AML: sustains MYC-dependent transcription.
- SCLC: essential for lineage-specific transcription factors.
2-2. Drug development
- SY-5609 (Syros Pharmaceuticals): selective CDK7 inhibitor, in trials for AML and solid tumors.
- CT7001 (Carrick Therapeutics): oral CDK7 inhibitor tested in breast and prostate cancer.
3. CDK8 — molecular mechanisms and disease relevance
CDK8, part of the Mediator complex, modulates transcription driven by transcription factors and super-enhancers. This positions CDK8 as a regulator of oncogenic pathways.
3-1. Disease associations
- Colorectal cancer: amplifies WNT/β-catenin signaling.
- Leukemia: regulates STAT pathways.
- Breast cancer and melanoma: linked to super-enhancer activity.
3-2. Drug development
- Cortistatin A derivatives: selective CDK8 inhibitors.
- Senexin B: CDK8/19 inhibitor under development.
4. Clinical outcomes and limitations
CDK7 inhibitors show early efficacy signals in AML and SCLC, but systemic transcriptional suppression poses toxicity risks. CDK8 inhibitors remain largely preclinical but are promising as regulators of oncogenic transcription.
5. Research frontiers
- Pulse dosing of CDK7 inhibitors to enhance tumor selectivity.
- Combining CDK8 inhibition with checkpoint blockade to augment immunity.
- Targeting super-enhancers as a cancer-specific transcriptional vulnerability.
6. Future perspectives
CDK7 and CDK8 act as “gatekeepers” of transcription initiation. CDK7 has already advanced into clinical trials, while CDK8 represents a new frontier. Selective targeting of oncogenic dependencies will be key to therapeutic success.
My Commentary
I view CDK7 and CDK8 as unique entry points into cancer’s transcriptional vulnerabilities. CDK7 inhibitors may become first-in-class therapies, while CDK8 inhibitors, though earlier in development, hold promise as modulators of super-enhancer-driven transcription.
Next Episode
In Part 3, we will focus on CDK9, the key kinase for transcription elongation, and review both molecular mechanisms and the latest clinical trials.
This article was edited by the Morningglorysciences team.
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