Preclinical characterization of FHT-171, a first-in-class degrader targeting CREB-binding protein (CBP) in CBP-dependent solid tumors

The paralog lysine acetyltransferases CREB-binding protein (CBP) and E1A-binding protein P300 (EP300) function as transcriptional coactivators that regulate diverse cellular programs. Functional screens have revealed a bidirectional synthetic relationship between these two paralogs in tumor cell biology. This synthetic lethal relationship offers a therapeutic opportunity in selectively targeting CBP in EP300 -mutant as well as other CBP-dependent cancers. Herein, we present a comprehensive preclinical evaluation for a first-in-class, selective CBP degrader, FHT-171, designed to target transcriptional co-activator dependencies in solid tumors. Through a series of in vitro and in vivo studies, we characterize the compound's biochemical selectivity, cellular degradation kinetics, transcriptional impacts, antitumor efficacy and tolerability across multiple solid tumor models. These findings provide mechanistic and non-clinical translational insight into the therapeutic potential of CBP degradation and support further development of this novel modality for the treatment of CBP-dependent malignancies.