Summary The dynamic and reversible acetylation of proteins catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) is a major epigenetic regulatory mechanism of gene transcription 1 associated with multiple diseases. While HDAC inhibitors are approved to treat certain cancers, progress on the development of drug-like HAT inhibitors has lagged 2. The HAT paralogs p300 and CBP (p300/CBP) are key transcriptional co-activators essential for a multitude of cellular processes and also implicated in human pathological conditions, including cancer 3. Current p300/CBP HAT domain inhibitors including natural products, 4 bi-substrate analogs (Lys-CoA) 5 and the widely utilized C646 6, 7 lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like p300/CBP catalytic inhibitor. We show the first high resolution (1.95Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 is acetyl-CoA competitive. A-485 selectively inhibited proliferation across lineage-specific tumor types, including several hematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen sensitive and castrate resistant prostate cancer and inhibited tumor growth in a castration resistant xenograft model. These results demonstrate the feasibility of selectively targeting the catalytic activity of histone acetyltransferases.

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Antagonism of protein-protein interactions (PPIs) with small molecules is becoming more feasible as a therapeutic approach. However, successful PPI inhibitors tend to target proteins containing deep peptide-binding grooves or pockets as opposed to the much more common large, flat protein interaction surfaces. Here we review one of the most abundant PPI domains in the human proteome, the WD40 repeat domain (WDR), which has a central peptide-binding pocket. Recently, two WDR proteins, WDR5 and EED, have been successfully targeted by potent, specific, cell-active, drug-like chemical probes. Could WDRs represent a novel target class for drug discovery? While clinical validation remains to be seen, a cautious optimism is justified, considering the ubiquitous involvement of WDR proteins across multiple disease-associated pathways. The druggability and structural diversity of WDR binding pockets suggest that this prevalent domain class could open-up areas of biology that have so far resisted drug discovery efforts.