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

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

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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