New Series｜Latest Therapeutic Trends — The Transcription Machinery as a Cancer Drug Target (Part 1: Introduction — Overview of Transcription and CDK Families)

This series will explore the latest drug discovery trends targeting the transcriptional machinery. In Part 1, we provide an introduction: what transcription is, how CDKs regulate it, and why transcriptional CDKs are emerging as hot targets in oncology.

1. The core of life — what is transcription?

Life depends on “copying and executing information.” DNA is the blueprint, RNA the copied instruction sheet, and proteins the executed products. Transcription is the process of copying DNA into RNA. If DNA is an encyclopedia locked in a library, transcription is the act of photocopying selected pages.

1-1. RNA polymerase II and CTD phosphorylation

RNA polymerase II (Pol II) drives transcription. Its carboxy-terminal domain (CTD) contains repeats that undergo phosphorylation, regulating transcriptional stages:

• Ser5 phosphorylation: initiation, at the promoter.
• Ser2 phosphorylation: elongation, across the gene body.

CDKs act as the “traffic controllers,” deciding when and where Pol II moves forward.

2. CDK family overview — cell cycle vs transcription

CDKs (cyclin-dependent kinases) are activated by binding cyclins. They control either cell cycle progression or transcription regulation.

2-1. Cell cycle CDKs

CDK1, 2, 4, and 6 control the cell cycle. CDK4/6 inhibitors (palbociclib, abemaciclib) are already approved cancer drugs.

2-2. Transcriptional CDKs

CDK7, 8, 9, 11, 12, and 13 regulate transcription initiation, pausing, elongation, splicing, and DNA repair-related gene expression.

3. Why target transcriptional CDKs in cancer?

Cancer cells often show “transcriptional addiction” — the need to constantly produce oncogenic proteins such as MYC or MCL-1. Blocking transcriptional CDKs interrupts this supply chain, driving cancer cells to apoptosis.

4. Historical background — from cell cycle to transcription

In the 1990s, focus was on cell cycle CDKs, but toxicity limited success. After CDK4/6 inhibitors proved effective in the 2010s, research attention shifted to transcriptional CDKs. Advances in RNA-seq and chromatin biology revealed unique vulnerabilities in cancer.

5. Role map of transcriptional CDKs

• CDK7: TFIIH subunit, essential for initiation.
• CDK8: Mediator-associated kinase, modulating enhancer-driven transcription.
• CDK9: P-TEFb, key to pause release and elongation.
• CDK11: Splicing and pause-checkpoint (newly reported roles).
• CDK12/13: Maintenance of DNA repair gene transcription.

6. Latest research updates

Recent studies highlight: CDK11 in pause-checkpoints, CDK12 inhibition combined with PARP inhibitors, and CDK9–BRD4 crosstalk. These findings expand the therapeutic potential of transcriptional CDKs.

7. Roadmap of this series

The series will unfold as follows:

1. Introduction (this article)
2. CDK7 & CDK8 — transcriptional initiation
3. CDK9 — elongation bottleneck
4. CDK12 & CDK13 — DNA repair regulation
5. CDK11 — novel pause-checkpoint
6. BRD4 crosstalk and therapeutic vision

My Commentary

I believe the appeal of targeting transcriptional CDKs lies in exploiting cancer’s “addictions.” The challenge, however, is sparing normal cells that also require transcription. The key is identifying tumor-specific dependencies, such as oncogene addiction or DNA repair vulnerabilities, and selectively targeting them.

Next Episode

In Part 2, we will turn to CDK7 and CDK8, exploring their molecular roles and the latest clinical advances.

This article was edited by the Morningglorysciences team.

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