CBP/p300 (bromodomain)

Class

Small molecule CBP/p300 bromodomain inhibitor

Pathway

Epigenetic transcriptional coactivation (MYC and androgen-receptor-driven gene programs)

CBP (CREB-binding protein) and its close paralog p300 are transcriptional coactivators found in essentially all cells. They do not bind DNA directly but are recruited to gene regulatory regions by sequence-specific transcription factors, where they help assemble the machinery needed for gene transcription. A key feature of both proteins is a bromodomain, a module that recognizes acetylated lysine residues on histones and on transcription factors themselves, anchoring CBP/p300 at active chromatin. This coactivator function is exploited by several oncogenic transcriptional programs, most notably those driven by MYC and by the androgen receptor, both of which depend heavily on CBP/p300 to sustain high-level gene expression. Small molecules that occupy the bromodomain pocket displace CBP/p300 from acetylated marks, dampening the transcriptional output of these programs. This mechanism is of particular interest in prostate cancer, where androgen receptor signaling persists even after hormonal therapies, including in disease driven by receptor variants that no longer require testosterone binding but still depend on coactivators. It is also relevant to MYC-driven malignancies more broadly, where transcriptional amplification by super-enhancers relies on CBP/p300 recruitment. Because CBP/p300 sits downstream of multiple oncogenic drivers, inhibiting it offers a way to blunt several disease-relevant pathways through one target.