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. 2019 Oct 11;6(5):054702.
doi: 10.1063/1.5119336. eCollection 2019 Sep.

Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT

Anna S Gardberg  1 , Annissa J Huhn  1 , Richard Cummings  1 , Archana Bommi-Reddy  1 , Florence Poy  1 , Jeremy Setser  2 , Valerie Vivat  1 , Francois Brucelle  2 , Jonathan Wilson  1
Affiliations

Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT

Anna S Gardberg et al. Struct Dyn. .

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.

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Figures

FIG. 1.
FIG. 1.
Three classes of epigenetic regulators. Writers add chemical modifications onto chromatin. Readers recognize chemical modifications on chromatin and bind to them. Erasers remove chemical modifications from chromatin. The action of each class controls the expression of certain genes in different ways. Reproduced with permission from Constellation's website.
FIG. 2.
FIG. 2.
Crystals of p300‐HAT‐YF‐Δloop with CoA and CPI-090.
FIG. 3.
FIG. 3.
Lys-CoA dual substrate analog P300-HAT structure 3BIY superposed with the CPI-090 P300-HAT structure (yellow C atoms for CPI-090 and CoA). Lys's closest approach to CPI-090 is ∼8 Å.
FIG. 4.
FIG. 4.
Comparing the binding modes of CPI-090 (yellow C-atoms) with CPI-076 (salmon C-atoms).
FIG. 5.
FIG. 5.
CPI-076-p300-HAT-CoA (light blue C atoms for the compound, green protein, and CoA) aligned with p300-HAT-CoA (pink protein and CoA) shows minimal perturbations in the protein backbone, as compound binding acts to displace five water molecules found in the CoA-only structure. Water molecules colored to match protein color.
FIG. 6.
FIG. 6.
(a) CPI-076 offered two vectors for structure-based elaboration. (b) The indole compound CPI-090, a stronger HAT inhibitor, offered vectors for optimization from the 4, 5, and 6 positions of the pyridine ring.
FIG. 7.
FIG. 7.
Inhibition of P300-HAT and P300-FL by CPI-090.
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