In Parts 1 and 2, we introduced CDK7 and CDK8 in transcription initiation. Here in Part 3, we focus on CDK9, the central kinase controlling the transition from paused RNA polymerase II (Pol II) to productive elongation. Among transcriptional CDKs, CDK9 is the most actively advanced in clinical drug development.
1. CDK9 molecular basis — P-TEFb and pause-release
Following initiation, Pol II undergoes promoter-proximal pausing, a checkpoint before elongation. CDK9, together with cyclin T, forms P-TEFb, which phosphorylates Pol II CTD at serine 2, releasing pausing factors (NELF, DSIF) and enabling elongation.
1-1. Components
- CDK9: catalytic subunit responsible for phosphorylation.
- Cyclin T1/T2: regulatory partners stabilizing CDK9.
- Regulators: HEXIM1 and 7SK snRNP sequester inactive P-TEFb.
2. Disease relevance — transcriptional addiction
Cancer cells rely on continuous expression of short-lived oncogenic proteins such as MCL-1 and MYC. This dependency is particularly evident in hematologic malignancies, including AML, T-cell lymphomas, and DLBCL. Solid tumors such as prostate, SCLC, and breast cancers also show potential CDK9 dependency.
3. Drug discovery history
3-1. Early multi-CDK inhibitors
Agents like flavopiridol and dinaciclib inhibited CDK9 along with other CDKs, showing activity but with high toxicity (bone marrow suppression, hepatotoxicity).
3-2. First-generation selective inhibitors
SNS-032 and alvocidib attempted to focus on CDK9 but were limited by pharmacokinetics and tolerability issues.
3-3. Second-generation selective inhibitors
- AZD4573 (AstraZeneca): A highly selective CDK9 inhibitor tested in hematologic cancers, achieving partial and complete responses in PTCL.
- VIP152 (Vincerx Pharma): A next-generation inhibitor with improved selectivity, under evaluation in AML and lymphomas.
4. Clinical outcomes and limitations
AZD4573 demonstrated efficacy in relapsed/refractory hematologic malignancies but also significant toxicities (bone marrow suppression, hepatic dysfunction, infections). VIP152 aims to improve tolerability while maintaining potency, with early data showing partial responses and stable disease.
5. Resistance mechanisms
- BRD4 reactivation providing alternative pause-release routes.
- BCL-2 family compensation sustaining survival despite MCL-1 suppression.
- Transcriptional reprogramming allowing adaptive resistance.
Combination therapies, particularly with the BCL-2 inhibitor venetoclax, are being investigated to overcome resistance.
6. Recent advances
- Pulse dosing schedules reduce toxicity while preserving efficacy.
- CDK9 inhibition combined with checkpoint inhibitors enhances immune responses.
- Dual inhibition of CDK9 and BRD4 shows synergistic suppression of transcriptional addiction.
7. Future perspectives
CDK9 represents the flagship of transcriptional CDK drug discovery. Moving forward, efforts will focus on mitigating toxicity, rational drug combinations, and expanding applications from hematologic cancers to solid tumors.
My Commentary
I consider CDK9 inhibitors the most advanced front of transcriptional CDK therapy. Exploiting tumor dependence on short-lived oncogenic proteins is promising, but systemic risks remain. The path forward will require integrated strategies — selective dosing, combination therapies, and innovative delivery systems.
Next Episode
In Part 4, we will focus on CDK12 and CDK13, which safeguard DNA repair gene expression, and explore synthetic lethality with PARP inhibitors in cancer therapy.
This article was edited by the Morningglorysciences team.
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