CBP and p300 are highly homologous coactivators which promote gene transcription by bridging between DNA-binding transcription factors and the basal transcription machinery, by providing a scaffold for integrating transcription factors, and by modifying transcription factors and chromatin through acetylation[2]. CBP/p300-IN-1 is a CBP/EP300 bromodomain (BRD) inhibitor（BDIs）[1]. The presence of amyloid-like aggregates coincides with increased cytotoxicity, and cell viability can be restored upon co-treating cells with small-molecule p300/CBP BDIs, which reflect reduced levels of protein aggregates. p300/CBP BDIs impede aggregation, which coincides with enhanced UPS function and increased cell viability[3]. CBP/EP300 bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 bromodomain inhibition[4]. In preclinical tumor models, in vivo administration of a CBP/EP300-BRD inhibitor (CBP/EP300-BRDi) alters intratumoral MDSCs and attenuates established tumor growth in immunocompetent tumor-bearing mice, as well as in MDSC-dependent xenograft models. Inhibition of CBP/EP300-BRD redirects tumor-associated MDSCs from a suppressive to an inflammatory phenotype through downregulation of STAT pathway-related genes and inhibition of Arg1 and iNOS. Similarly, CBP/EP300-BRDi decreases differentiation and suppressive function of human MDSCs in vitro[5].
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