The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription1 and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind2. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer3). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products4, bi-substrate analogues5 and the widely used small molecule C6466,7, lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.
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Gene Expression Omnibus
Protein Data Bank
Protein Data Bank
We thank V. Abraham and M. Smith for high content microscopy assistance; S. Ackler, D. He, Z. Yang and R. Bellin for assistance with cell proliferation assays; H. Liu for assistance with pharmacokinetic analyses; G. Diaz for help with compound selectivity screening; R. Henry for compound X-ray crystallography assistance; and E. Corey for the LuCap-77 CR patient derived xenograft model. Eurofins-Cerep supplied HAT selectivity, 7TM and ion channel off-target selectivity screening. Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical Research Institute. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. C.C. is supported by the Hallas Møller Investigator award from the Novo Nordisk Foundation (NNF14OC0008541). The Novo Nordisk Foundation Center for Protein Research is supported financially by the Novo Nordisk Foundation (Grant agreement NNF14CC0001). P.A.C. was supported by the NIH and FAMRI foundation. R.M. is supported by the NIH.
Extended data figures
Comparison of IC50 values for inhibition of p300 acetyltransferase activity by A-485 and literature reported p300/CBP tool compounds
Percent inhibition of activity of the indicated HATs by A-485
IC50 values of binding of the indicated bromodomains by A-485
Percent binding of the indicated non-epigenetic proteins by A-485 and A-486
Percent inhibition of activity of the indicated non-epigenetic proteins by A-485 and A-486
IC50 values of binding of the indicated kinases by A-485
EC50 values for inhibition of histone acetyl marks upon treatment with the indicated compounds
Acetylation sites on the CBP/p300 auto-acetylation loop (ref 13), and their regulation by A-485 in HeLa cells
EC50 values for inhibition of proliferation of cancer cell lines by A-485
Number of significant gene expression changesa induced by A-485 treatment for 6 hours in prostate cancer cells
PK profile of A-485 after a single intraperitoneal dose
Plasma and brain exposures 24 h post a single oral dose of A-485
Antibodies used in this study
IDT PrimeTime qPCR assay primer and probe sequences used in this study for qPCR assays
Primer sequences used in this study for ChIP qPCR assays