Discovery of a First-in-Class Murine Double Minute 2-Recruiting Positive Transcription Elongation Factor B PROTAC...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The positive transcription elongation factor b (P-TEFb) complex, comprising CDK9 and cyclin T, is crucial for gene transcription and a promising oncology target.
• Developing selective CDK9 inhibitors has been challenging due to difficulties in achieving clinical efficacy.
• Targeting CDK9 is vital, but requires novel strategies beyond simple inhibition.

Purpose of the Study:

• To design and evaluate novel P-TEFb degraders for cancer therapy.
• To develop a compound that recruits MDM2 E3 ligase for targeted protein degradation.
• To assess the efficacy and safety of a lead P-TEFb degrader (dCDK9-010) in preclinical cancer models.

Main Methods:

• Conjugation of a CDK9 inhibitor (SNS032) with an MDM2 ligand (RG7388) to create P-TEFb degraders.
• Utilizing MDM2 E3 ligase to induce proteasome-dependent degradation of CDK9 and cyclin T isoforms.
• Evaluating compound 13 (dCDK9-010) in diverse cancer cell lines and murine xenograft models (lung cancer, Ewing sarcoma).
• Assessing inhibition of RNA polymerase II phosphorylation and MDM2-mediated p53 degradation.

Main Results:

• Compound dCDK9-010 effectively degrades CDK9 and all cyclin T isoforms via MDM2 recruitment.
• dCDK9-010 inhibits RNA polymerase II phosphorylation and activates the p53 pathway by blocking p53 degradation.
• Selective cytotoxicity was observed in TP53 wild-type cancer cells, sparing TP53-mutant and nonmalignant cells.
• Significant tumor growth inhibition and an excellent safety profile were demonstrated in preclinical models.

Conclusions:

• dCDK9-010 represents a first-in-class, selective MDM2-recruiting P-TEFb degrader.
• This MDM2-recruiting degradation strategy enables the elimination of the entire P-TEFb complex.
• This approach offers a promising new therapeutic paradigm for TP53 wild-type cancers.