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Nature. 2017 Oct 5;550(7674):128-132. doi: 10.1038/nature24028. Epub 2017 Sep 27.

Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.

Author information

1
Discovery, Global Pharmaceutical Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, USA.
2
eFFECTOR Therapeutics, 11180 Roselle St, Suite A, San Diego, California 92121, USA.
3
Petra Pharma Corporation, 430 E. 29th St, Suite 435, New York, New York 10016, USA.
4
Faraday Pharmaceuticals, 1616 Eastlake Ave E., Suite 560, Seattle, Washington 98102, USA.
5
Department of Proteomics, the Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
6
Cascadian Therapeutics, Inc., 2601 Fourth Avenue, Suite 500, Seattle, Washington 98121, USA.
7
Van Drie Research, 109 Millpond, Andover, Massachusetts 01845, USA.
8
Accelerator Corporation, 430 East 29th St, New York, New York 10106, USA.
9
Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, Philadelphia, Pennsylvania 19104, USA.
10
Johns Hopkins University, 725 N. Wolfe St, Baltimore, Maryland 21205, USA.

Abstract

The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription 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 behind. 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 cancer). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products, bi-substrate analogues and the widely used small molecule C646, 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.

PMID:
28953875
PMCID:
PMC6050590
DOI:
10.1038/nature24028
[Indexed for MEDLINE]
Free PMC Article

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