Structure-guided design of JZY3032, a dual-engaging DALTAC that miswires AR-p300 in prostate cancer

Chemical-induced proximity (CIP) strategies have expanded the therapeutic landscape by modulating protein-protein interactions, yet most current modalities, such as PROTACs and molecular glues-juxtapose non-physiological partners, often yielding variable or unpredictable outcomes. To address this limitation, we developed Domain-ALTeration Chimeras (DALTACs), a mechanistically distinct platform that selectively miswires endogenous protein complexes by enforcing non-productive domain-domain interactions between physiologic partners. Rather than degrading targets or stabilizing native interfaces, DALTACs reconfigure the topology of multi-domain complexes through rational ligand selection and linker engineering. As a proof of concept, we designed JZY3032, the first-in-class AR-p300 DALTAC, to disable the androgen receptor (AR)-p300 transcriptional complex, a critical regulatory node in prostate cancer. Guided by iterative medicinal-chemistry optimization, we conjugated an AR LBD inhibitor to a selective p300 bromodomain inhibitor using a tunable linker optimized for cooperative, simultaneous dual engagement. The resulting construct redirects the physiological AR-p300 interaction surface into a sterically misaligned, non-productive configuration, thereby preventing AR N-terminal domain communication with p300 and suppressing enhancer activation. Mechanistic specificity was confirmed using two negative-control analogs that selectively disrupt AR or p300 binding; both lacked biological activity, demonstrating that dual engagement and domain-reconfiguration are required for DALTAC function. SAR studies revealed that linker length, rigidity, and exit-vector orientation are key determinants of complex miswiring efficiency. Functionally, JZY3032 potently inhibits growth of AR- and p300-co-dependent prostate cancer models while sparing AR-negative lineages, establishing the lineage-selective therapeutic potential arising from engineered domain miswiring. Collectively, these data establish DALTACs as a new class of proximity-based therapeutics capable of disabling oncogenic transcriptional complexes through topology engineering. JZY3032 exemplifies a broadly extensible, modular chemistry platform for rationally designing future DALTAC molecules targeting diverse disease-relevant protein assemblies.