CBP (CREB-binding protein) and EP300 (p300) bromodomains

Class

Small-molecule CBP/p300 bromodomain inhibitor

Pathway

Orally active inhibitor of the CBP/EP300 bromodomain, disrupting these transcriptional coactivators' role in oncogenic gene-expression programs

CBP (CREB-binding protein) and its close relative EP300 (p300) are transcriptional coactivators: proteins that do not bind DNA directly but assemble at gene-regulatory regions to help switch genes on. They carry a bromodomain, a structural module that recognizes acetylated lysine residues on histone proteins, and they use this reader function to anchor themselves, along with transcription factors and RNA polymerase machinery, at active enhancers and promoters. Many cancers become dependent on strong, continuous transcription of specific driver genes, and CBP/p300 frequently participate in sustaining these programs, including those driven by androgen receptor signaling in prostate cancer and MYC-driven transcription in various tumor types. A small-molecule inhibitor that blocks the bromodomain, rather than the enzyme's separate acetyltransferase activity, aims to selectively displace CBP/p300 from these oncogenic complexes without broadly shutting down the protein's other catalytic functions. Because CBP and p300 substantially overlap in function, agents are typically designed to inhibit both paralogs, since blocking only one might be compensated by the other. This mechanism is being explored primarily in cancers where transcriptional dependency on these coactivators has been demonstrated, including certain prostate and hematologic malignancies.