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

ABSTRACT 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.