Design and evaluation of selective BET PROTACs with potent antitumor efficacy and safety against acute myeloid...

Targeting bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for acute myeloid leukemia (AML). However, clinical development of conventional BET inhibitors has been limited by dose-related toxicities and compensatory resistance. Proteolysis-targeting chimeras (PROTACs) offer a catalytic and often more selective alternative by degrading target proteins via the ubiquitin-proteasome system. In this work, we designed and synthesized a series of novel BET PROTACs based on the clinical inhibitor ABBV-075. Through systematic optimization of linker length/composition and E3 ligase ligands (CRBN or VHL), we identified two highly potent PROTACs, A10 (CRBN-based) and A12 (VHL-based). Both compounds effectively degraded BET proteins, inhibited cell proliferation, induced cell-cycle arrest, and promoted apoptosis in MV4-11 AML cells. In MV4-11 xenograft models, A10 (6 mg/kg) and A12 (2 mg/kg) demonstrated significant tumor growth inhibition (76.2% and 60.5%, respectively). A comprehensive drug-likeness assessment revealed that while A12 exhibited higher systemic exposure in pharmacokinetic studies, A10 displayed a markedly superior safety profile with minimal hepatorenal toxicity. The favorable efficacy-safety balance of A10 underscores its strong potential as a preclinical candidate for AML therapy. This study highlights how rational PROTAC optimization can yield degraders with enhanced therapeutic windows, providing a promising path forward for targeted protein degradation in AML.