From Part 1 through Part 5, we explored CDK7/8/9/12/13/11 and their roles in transcriptional regulation. In this final installment, we turn to BRD4, a pivotal co-regulator that interacts closely with CDKs and controls super-enhancer–driven transcription.
1. What is BRD4?
BRD4 belongs to the BET protein family and binds to acetylated histones to activate transcription. At super-enhancers, BRD4 sustains oncogene addiction, making tumors highly dependent on its activity.
2. Crosstalk with CDKs
BRD4 recruits CDK9 within the P-TEFb complex to release paused RNA Pol II. It also indirectly interacts with CDK7/12, influencing transcriptional initiation and DNA repair gene expression.
- BRD4 → CDK9: promotes pause release.
- BRD4 → CDK7/12: affects CTD phosphorylation and DNA repair transcription.
- Super-enhancers: reinforce oncogene dependence (e.g., MYC, BCL2).
3. BET inhibitors
Several BET inhibitors have been developed to block BRD4 activity:
- JQ1: pioneering tool compound.
- Pelabresib (CPI-0610): in clinical trials for myelofibrosis and lymphomas.
- BMS-986158: in development for solid tumors.
4. Clinical outcomes and challenges
BET inhibitors demonstrated early promise, yet challenges remain:
- Toxicities such as thrombocytopenia and fatigue.
- Resistance mechanisms activating alternative pathways.
- Durability issues with prolonged dosing.
5. Combination strategies with CDK inhibitors
- BRD4 + CDK9: dual blockade of pause release and elongation.
- BRD4 + CDK12: simultaneous targeting of DNA repair and super-enhancer programs.
- Triple combinations: BRD4 + CDK9 + BCL2 inhibition in MCL1-dependent cancers.
6. Clinical significance of super-enhancer targeting
Super-enhancers are often described as cancer’s “Achilles’ heel.” BRD4 sits at their core, and pairing BET inhibitors with CDK inhibitors may enhance tumor selectivity while minimizing toxicity.
7. Future perspectives
- Next-generation BET inhibitors: with improved safety and selectivity.
- PROTAC degraders: directly eliminating BRD4 protein.
- Immunotherapy combinations: boosting anti-tumor responses by disrupting super-enhancer programs.
My Commentary
I regard BRD4 as the “traffic coordinator” for CDKs in transcription. While BET inhibitors alone face challenges, combined strategies with CDK9 or CDK12 inhibitors could bring selective cancer targeting closer to reality.
Series Conclusion
This article marks the conclusion of the series “Latest Therapeutic Trends — The Transcription Machinery as a Cancer Drug Target.” Across six parts, we traced the emerging landscape of transcriptional CDKs and BRD4 in drug discovery. The key takeaway is that transcriptional regulation is not dictated by a single kinase but by a coordinated relay. Future therapies will likely need to exploit this network complexity, targeting multiple nodes simultaneously.
This article was edited by the Morningglorysciences team.
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