Discovery of ZX079 as a Dual PROTAC Degrader Targeting BRD4/CBP in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is driven by transcriptional plasticity and epigenetic dysregulation. While BET proteins have emerged as promising therapeutic targets, BET inhibitors are limited by modest clinical efficacy and resistance, potentially mediated by CBP/p300-driven compensatory mechanisms. Herein, we describe the design, synthesis, and biological evaluation of a novel series of dual BRD4/CBP PROTAC degraders. The lead compound, 10k (ZX079), induces potent, dose- and time-dependent degradation of BRD4 and CBP and demonstrates superior suppression of oncogenic transcription and inhibition of AML cell proliferation compared with the dual BET/CBP inhibitor NEO2734. In vivo, 10k significantly reduces tumor growth in an AML xenograft model with TGI over 90%. Collectively, these findings highlight dual degradation of BRD4 and CBP as a promising strategy for AML.