Discovery of a First-in-Class Murine Double Minute 2-Recruiting Positive Transcription Elongation Factor B PROTAC Degrader With Selective Antitumor Activity.

The positive transcription elongation factor b (P-TEFb) complex, composed of CDK9 and cyclin T isoforms (T1, T2a and T2b), is critical for gene transcription, positioning CDK9 as a very promising oncology target. However, the development of selective and clinically effective small-molecule CDK9 inhibitors has proven challenging. To overcome this limitation, we designed a series of highly efficient and selective P-TEFb degraders by conjugating the CDK9 inhibitor SNS032 with the mouse double minute 2 (MDM2) ligand RG7388. Our lead compound, 13 (dCDK9-010), recruits the MDM2 E3 ligase to induce proteasome-dependent degradation of CDK9 and all cyclin T isoforms across diverse cancer models. dCDK9-010 potently inhibits RNA polymerase II carboxy-terminal repeat domain phosphorylation and blocks MDM2-mediated p53 degradation, resulting in concurrent p53 pathway activation. This dual mechanism drives selective cytotoxicity in TP53 wild-type cancer cells, sparing TP53-mutant or nonmalignant cells. In murine xenograft models of lung cancer and Ewing sarcoma, intravenous dCDK9-010 administration significantly inhibited tumor growth while demonstrating an excellent safety profile. Collectively, this study establishes dCDK9-010 as a first-in-class, selective MDM2-recruiting P-TEFb degrader. By enabling the elimination of the entire P-TEFb complex, this MDM2-recruiting degradation strategy expands the toolkit for targeting CDK9 and represents a promising new therapeutic paradigm for TP53 wild-type cancers.