The transcriptional coactivators p300 and CREB-binding protein (CBP) have emerged as central regulators of enhancer-mediated transcription and key epigenetic integrators of oncogenic signaling in cancer. Through their histone acetyltransferase activity, particularly the deposition of histone H3 lysine 27 acetylation (H3K27ac), p300/CBP control enhancer activation and coordinate transcriptional programs that govern cell identity, tumor progression, and therapeutic response. Dysregulation of enhancer activity is increasingly recognized as a fundamental mechanism driving oncogenic transcription across diverse malignancies. Recent advances in chemical biology have enabled pharmacological targeting of p300/CBP through several complementary strategies, including catalytic histone acetyltransferase (HAT) inhibitors, bromodomain (BRD) inhibitors, dual BET–p300 inhibitors, and emerging targeted protein degradation approaches. In this review, we summarize the molecular functions of p300/CBP, recent progress in the development of pharmacological agents targeting these coactivators, and the current landscape of clinical translation. Catalytic inhibition of p300/CBP directly suppresses H3K27ac and provides a measurable tumor pharmacodynamic biomarker, whereas alternative targeting modalities modulate enhancer-driven transcription through distinct molecular mechanisms. Early-phase clinical studies indicate that p300-directed agents can achieve pharmacodynamic modulation in patients. We further discuss the translational relevance of p300 targeting in osteosarcoma, a malignancy characterized by genomic instability and heterogeneous transcriptional states rather than dominant kinase mutations. Collectively, these findings position p300 catalytic inhibition as a mechanistically defined and pharmacologically tractable strategy for targeting enhancer-driven oncogenic transcription and support continued clinical development of p300-directed therapies.
Masuda et al. (Mon,) studied this question.