Abstract
Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the dynamic and reversible acetylation of proteins, an epigenetic regulatory mechanism associated with multiple cancers. Indeed, HDAC inhibitors are already approved in the clinic. The HAT paralogs p300 and CREB-binding protein (CBP) have been implicated in human pathological conditions including several hematological malignancies and androgen receptor-positive prostate cancer. Others have reported CoA-competitive inhibitors of p300 and CBP with cell-based activity. Here, we describe 2 compounds, CPI-076 and CPI-090, discovered through p300-HAT high throughput screening screening, which inhibit p300-HAT via binding at an allosteric site. We present the high resolution (1.7 and 2.3 Å) co-crystal structures of these molecules bound to a previously undescribed allosteric site of p300-HAT. Derivatization yielded actionable structure-activity relationships, but the full-length enzymatic assay demonstrated that this allosteric HAT inhibitor series was artifactual, inhibiting only the HAT domain of p300 with no effect on the full-length enzyme.
Highlights
Epigenetics refers to a broad regulatory system that controls gene expression by modifying chromatin
Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the dynamic and reversible acetylation of proteins, an epigenetic regulatory mechanism associated with multiple cancers
We present the high resolution (1.7 and 2.3 A ) co-crystal structures of these molecules bound to a previously undescribed allosteric site of p300-HAT
Summary
Epigenetics refers to a broad regulatory system that controls gene expression by modifying chromatin. Various chromatin regulatory mechanisms (multiple classes of reader, writer, and eraser proteins) impact the chromatin structure to alter the transcriptional machinery’s access to DNA (Jenuwein and Allis, 2001). Epigenetic regulators within the writer, reader, and eraser classes modify chromatin and affect gene expression by adding, binding to, or removing chemical tags, which are indicated by dots, on chromatin. In normal cells, these epigenetic mechanisms are tightly regulated so that genes are “turned on” or “turned off” as appropriate. (1) Small-molecule inhibitors can block the abnormal function of epigenetic regulators that cancer cells depend on for growth and potentially restore normal gene expression. Crystallography was key to unraveling these observations by revealing that these inhibitors occupied a previously undescribed allosteric pocket
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