Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours
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Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. / Lasko, Loren M; Jakob, Clarissa G; Edalji, Rohinton P; Qiu, Wei; Montgomery, Debra; Digiammarino, Enrico L; Hansen, T Matt; Risi, Roberto M; Frey, Robin; Manaves, Vlasios; Shaw, Bailin; Algire, Mikkel; Hessler, Paul; Lam, Lloyd T; Uziel, Tamar; Faivre, Emily; Ferguson, Debra; Buchanan, Fritz G; Martin, Ruth L; Torrent, Maricel; Chiang, Gary G; Karukurichi, Kannan; Langston, J William; Weinert, Brian T; Choudhary, Chunaram; de Vries, Peter; Van Drie, John H; McElligott, David; Kesicki, Ed; Marmorstein, Ronen; Sun, Chaohong; Cole, Philip A; Rosenberg, Saul H; Michaelides, Michael R; Lai, Albert; Bromberg, Kenneth D.
In: Nature, Vol. 550, No. 7674, 05.10.2017, p. 128-132.Research output: Contribution to journal › Journal article › Research › peer-review
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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 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.
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 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.
U2 - 10.1038/nature24028
DO - 10.1038/nature24028
M3 - Journal article
C2 - 28953875
VL - 550
SP - 128
EP - 132
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7674
ER -
ID: 184291511