JZY3032

JZY3032 is a first-in-class Domain-ALTeration Chimera (DALTAC) designed to disable the androgen receptor (AR)-p300 transcriptional complex, a critical regulatory node in prostate cancer. Developed at the University of Michigan, JZY3032 is a bifunctional small molecule that conjugates an AR ligand-binding domain (LBD) inhibitor to a selective p300 bromodomain inhibitor via a tunable linker optimized for cooperative, simultaneous dual engagement. Unlike PROTACs or molecular glues that typically induce protein degradation or stabilize native interfaces, JZY3032 reconfigures the topology of the AR-p300 complex into a sterically misaligned, non-productive configuration. This engineered 'miswiring' prevents communication between the AR N-terminal domain and p300, thereby suppressing enhancer activation and potently inhibiting the growth of AR- and p300-co-dependent prostate cancer models while sparing AR-negative lineages.