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

TY - JOUR

T1 - Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours

AU - Lasko, Loren M

AU - Jakob, Clarissa G

AU - Edalji, Rohinton P

AU - Qiu, Wei

AU - Montgomery, Debra

AU - Digiammarino, Enrico L

AU - Hansen, T Matt

AU - Risi, Roberto M

AU - Frey, Robin

AU - Manaves, Vlasios

AU - Shaw, Bailin

AU - Algire, Mikkel

AU - Hessler, Paul

AU - Lam, Lloyd T

AU - Uziel, Tamar

AU - Faivre, Emily

AU - Ferguson, Debra

AU - Buchanan, Fritz G

AU - Martin, Ruth L

AU - Torrent, Maricel

AU - Chiang, Gary G

AU - Karukurichi, Kannan

AU - Langston, J William

AU - Weinert, Brian T

AU - Choudhary, Chunaram

AU - de Vries, Peter

AU - Van Drie, John H

AU - McElligott, David

AU - Kesicki, Ed

AU - Marmorstein, Ronen

AU - Sun, Chaohong

AU - Cole, Philip A

AU - Rosenberg, Saul H

AU - Michaelides, Michael R

AU - Lai, Albert

AU - Bromberg, Kenneth D

PY - 2017/10/5

Y1 - 2017/10/5

N2 - The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription1 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 behind2. 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 cancer3). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products4, bi-substrate analogues5 and the widely used small molecule C6466,7, 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.

AB - The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription1 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 behind2. 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 cancer3). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products4, bi-substrate analogues5 and the widely used small molecule C6466,7, 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.

U2 - 10.1038/nature24028

DO - 10.1038/nature24028

M3 - Journal article

C2 - 28953875

SN - 0028-0836

VL - 550

SP - 128

EP - 132

JO - Nature

JF - Nature

IS - 7674

ER -