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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Loren M Lasko
  • Clarissa G Jakob
  • Rohinton P Edalji
  • Wei Qiu
  • Debra Montgomery
  • Enrico L Digiammarino
  • T Matt Hansen
  • Roberto M Risi
  • Robin Frey
  • Vlasios Manaves
  • Bailin Shaw
  • Mikkel Algire
  • Paul Hessler
  • Lloyd T Lam
  • Tamar Uziel
  • Emily Faivre
  • Debra Ferguson
  • Fritz G Buchanan
  • Ruth L Martin
  • Maricel Torrent
  • Gary G Chiang
  • Kannan Karukurichi
  • J William Langston
  • Brian T Weinert
  • Peter de Vries
  • John H Van Drie
  • David McElligott
  • Ed Kesicki
  • Ronen Marmorstein
  • Chaohong Sun
  • Philip A Cole
  • Saul H Rosenberg
  • Michael R Michaelides
  • Albert Lai
  • Kenneth D Bromberg

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.

Original languageEnglish
Issue number7674
Pages (from-to)128-132
Number of pages5
Publication statusPublished - 5 Oct 2017

ID: 184291511