Discovery of CZL-149: A Novel, Highly Potent, and Orally Bioavailable Dual Inhibitor Targeting BET and p300/CBP Bromodomains with Strong Antitumor Efficacy.

Dual inhibition of bromodomain and extra terminal (BET) and E1A-binding protein (p300)/CREB-binding protein (CBP) bromodomains has shown superior antiproliferative activity compared to selectively targeting either family alone. Despite this therapeutic promise, progress in developing dual BET and p300/CBP bromodomain inhibitors remains limited, with only one candidate, NEO2734, having advanced to clinical studies. In this study, we replaced the pyridone-based acetyl-lysine mimic in NEO2734 with a pyrrolo[2,3-c]pyridinone fragment, which engages a conserved asparagine residue via a bidentate hydrogen-bond interaction. Through systematic structure-activity relationship exploration, we identified CZL-149, which exhibits potent activity against BET and p300/CBP bromodomains as well as multiple myeloma OPM-2 cells (IC50 = 3.3 nM). CZL-149 displays favorable drug-like properties and metabolic profile, achieving 107% oral bioavailability in mice. Importantly, CZL-149 outperformed NEO2734 in both antitumor efficacy (TGI = 78%) and safety in vivo, highlighting its potential as an advanced preclinical candidate worthy of further development.