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

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; Chunaram Choudhary; 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

doi:10.1038/nature24028

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

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 TorrentGary G Chiang, Kannan Karukurichi, J William Langston, Brian T Weinert, Chunaram Choudhary, 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

213 Citations (Scopus)

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 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.

Original language	English
Journal	Nature
Volume	550
Issue number	7674
Pages (from-to)	128-132
Number of pages	5
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature24028
Publication status	Published - 5 Oct 2017

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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., ... Bromberg, K. D. (2017). Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature, 550(7674), 128-132. https://doi.org/10.1038/nature24028

Lasko, LM, Jakob, CG, Edalji, RP, Qiu, W, Montgomery, D, Digiammarino, EL, Hansen, TM, Risi, RM, Frey, R, Manaves, V, Shaw, B, Algire, M, Hessler, P, Lam, LT, Uziel, T, Faivre, E, Ferguson, D, Buchanan, FG, Martin, RL, Torrent, M, Chiang, GG, Karukurichi, K, Langston, JW, Weinert, BT , Choudhary, C, de Vries, P, Van Drie, JH, McElligott, D, Kesicki, E, Marmorstein, R, Sun, C, Cole, PA, Rosenberg, SH, Michaelides, MR, Lai, A & Bromberg, KD 2017, 'Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours', Nature, vol. 550, no. 7674, pp. 128-132. https://doi.org/10.1038/nature24028

@article{d4fcc7ea8ef74b9ea0b82959326335fd,

title = "Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours",

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 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 {\AA}) 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.",

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

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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 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 -

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

Abstract

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