The transcriptional coactivators p300 and CBP (CREB-binding protein) play a central role in gene regulation by functioning as histone acetyltransferases and scaffolding proteins that facilitate chromatin remodeling and transcriptional activation [[1], [2], [3], [4], [5]]. These proteins interact with a wide array of transcription factors, thereby influencing the expression of genes involved in crucial cellular processes such as proliferation, differentiation, and apoptosis. The structurally conserved transcriptional coactivators p300 and CBP (KAT3B/KAT3A) constitute essential epigenetic regulators that orchestrate chromatin remodeling through their intrinsic histone acetyltransferase (HAT) activity, mediating lysine acetylation on both histone (H3K18/K27) and non-histone substrates including p53, STAT3, and nuclear receptors. These enzymes serve as transcriptional integrators, bridging enhancer-bound transcription factors with the basal transcriptional machinery. By modulating chromatin accessibility and recruiting co-regulators, p300/CBP control the expression of genes involved in diverse cellular processes such as proliferation, differentiation, metabolism, apoptosis, and DNA damage response. Their regulatory influence extends across numerous signaling pathways—including Wnt, Notch, and TGF-β—and is essential for maintaining normal tissue homeostasis and developmental fidelity. Their catalytic MYST domains facilitate chromatin decompaction via ε-amino acetylation, enabling transcriptional activation of proliferation- and differentiation-related genes while maintaining genomic stability. Their catalytic MYST domains facilitate chromatin decompaction via ε-amino acetylation, enabling transcriptional activation of proliferation- and differentiation-related genes while maintaining genomic stability [[6], [7], [8], [9]]. Mechanistic studies reveal that p300/CBP's multidomain architecture-comprising TAZ, ZZ, and KIX domains - permits allosteric regulation of their HAT activity through competitive binding with transcription factors like CREB and HIF-1α [10].

The dysregulation of p300/CBP enzymatic activity manifests through multiple oncogenic mechanisms across diverse malignancies, with genomic amplification and somatic mutations (EP300 R1627W) driving tumorigenesis via transcriptional activation of oncogenic programs (YAP1, E2F2, MYC) [4,[11], [12], [13], [14], [15], [16], [17], [18], [19], [20]]. Structural biology studies reveal a conserved catalytic mechanism where Y1467 facilitates acetyl transfer through general acid catalysis, while the bromodomain exhibits exquisite acetyllysine recognition via a hydrogen bond network involving N1168 and water-mediated interactions with P1110/Y1125 (ΔG = −9.3 kcal/mol) [[21], [22], [23]]. Five structurally conserved water molecules in the ZA channel contribute to ligand binding entropy (ΔS = +15.2 cal/mol·K), with the "LPF shelf" (L1106/P1110/F1113) and R1173 forming critical pharmacophore interactions for inhibitor design [20,[24], [25], [26]]. These structural insights have guided development of clinical candidates including A-485 and CCS1477, which exploit these binding features while addressing challenges of target redundancy [[27], [28], [29], [30]].

The critical involvement of p300/CBP in driving oncogenic transcriptional programs has firmly established them as high-value targets for cancer therapy. Aberrant activation of these epigenetic coactivators contributes to the dysregulation of key cancer-promoting genes, making pharmacological inhibition of their activity a promising strategy across a wide range of malignancies. In response, a growing pipeline of small-molecule inhibitors targeting p300/CBP has advanced into clinical development (Fig. 1 and Table 1) [29,[31], [32], [33], [34], [35]]. Three major therapeutic approaches have emerged: (1) competitive inhibitors of HAT catalytic activity, (2) bromodomain antagonists that disrupt acetyl-lysine reader functions, and (3) bifunctional degraders that induce selective proteasomal degradation of the target proteins [36,37]. Several compounds exemplify the rational design principles used to exploit structural features unique to p300/CBP. Pocenbrodib, for instance, was developed using structure-guided optimization to target the LPF shelf (L1106/P1110/F1113), significantly enhancing binding affinity. Meanwhile, the covalent inhibitor EP-31670 demonstrates high potency (kinact/Ki = 2800 M−1 s−1) through irreversible engagement with C1438 in the HAT domain [[31], [32], [33], [34], [35]]. Among the most clinically advanced agents is Inobrodib, currently undergoing Phase 1/2 trials in patients with hematologic malignancies and metastatic castration-resistant prostate cancer (mCRPC) (Fig. 1) [38].

This review systematically examines p300/CBP inhibitors reported from 2019, focusing on the medicinal chemistry optimization strategies employed in their development. The analysis encompasses structural modifications, pharmacokinetic enhancements, and selectivity improvements that transformed lead compounds into clinical candidates. Key binding modes with the target proteins, and critical biochemical data are thoroughly discussed.