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

  • Nature. 2017 Oct 5;550(7674):128-132. doi: 10.1038/nature24028.
Loren M Lasko  1 ,  Clarissa G Jakob  1 ,  Rohinton P Edalji  1 ,  Wei Qiu  1 ,  Debra Montgomery  1 ,  Enrico L Digiammarino  1 ,  T Matt Hansen  1 ,  Roberto M Risi  1 ,  Robin Frey  1 ,  Vlasios Manaves  1 ,  Bailin Shaw  1 ,  Mikkel Algire  1 ,  Paul Hessler  1 ,  Lloyd T Lam  1 ,  Tamar Uziel  1 ,  Emily Faivre  1 ,  Debra Ferguson  1 ,  Fritz G Buchanan  1 ,  Ruth L Martin  1 ,  Maricel Torrent  1 ,  Gary G Chiang  1  2 ,  Kannan Karukurichi  3 ,  J William Langston  4 ,  Brian T Weinert  5 ,  Chunaram Choudhary  5 ,  Peter de Vries  6 ,  John H Van Drie  7 ,  David McElligott  8 ,  Ed Kesicki  3 ,  Ronen Marmorstein  9 ,  Chaohong Sun  1 ,  Philip A Cole  10 ,  Saul H Rosenberg  1 ,  Michael R Michaelides  1 ,  Albert Lai  1 ,  Kenneth D Bromberg  1
Affiliations
  • 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.
PMID: 28953875 DOI: 10.1038/nature24028
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.

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