5KJ2

The novel p300/CBP inhibitor A-485 uncovers a unique mechanism of action to target AR in castrate resistant prostate cancer

Summary for 5KJ2

• Entry DOI: 10.2210/pdb5kj2/pdb
• Descriptor: Histone acetyltransferase p300, N-[(4-fluorophenyl)methyl]-2-{(1R)-5-[(methylcarbamoyl)amino]-2',4'-dioxo-2,3-dihydro-3'H-spiro[indene-1,5'-[1,3]oxazolidin]-3'-yl}-N-[(2S)-1,1,1-trifluoropropan-2-yl]acetamide, SODIUM ION, ... (4 entities in total)
• Functional Keywords: histone acetyltransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 40820.46

Authors

Jakob, C.G.,Qiu, W.,Edalji, R.P.,Sun, C. (deposition date: 2016-06-17, release date: 2017-09-27, Last modification date: 2023-09-27)

Primary citation

Lasko, L.M.,Jakob, C.G.,Edalji, R.P.,Qiu, W.,Montgomery, D.,Digiammarino, E.L.,Hansen, T.M.,Risi, R.M.,Frey, R.,Manaves, V.,Shaw, B.,Algire, M.,Hessler, P.,Lam, L.T.,Uziel, T.,Faivre, E.,Ferguson, D.,Buchanan, F.G.,Martin, R.L.,Torrent, M.,Chiang, G.G.,Karukurichi, K.,Langston, J.W.,Weinert, B.T.,Choudhary, C.,de Vries, P.,Van Drie, J.H.,McElligott, D.,Kesicki, E.,Marmorstein, R.,Sun, C.,Cole, P.A.,Rosenberg, S.H.,Michaelides, M.R.,Lai, A.,Bromberg, K.D.
Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.
Nature, 550:128-132, 2017

PubMed 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.

PubMed: 28953875
DOI: 10.1038/nature24028

Experimental method

X-RAY DIFFRACTION (1.95 Å)