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Ref Type Journal Article
PMID (28953875)
Authors 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
Title Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.
Journal Nature
Vol 550
Issue 7674
Date 2017 Oct 05
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
A-485 A-485 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
A-485 A-485 is a selective histone acetyltransferase inhibitor of EP300 and CREBBP, which induces cellular senescence, and may result in decreased cell proliferation and inhibition of tumor growth (PMID: 28953875, PMID: 30266801).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown non-Hodgkin lymphoma not applicable A-485 Preclinical - Cell culture Actionable In a preclinical study, A-485 treatment inhibited proliferation in non-Hodgkin lymphoma cell lines in culture (PMID: 28953875). 28953875
Unknown unknown acute myeloid leukemia not applicable A-485 Preclinical - Cell culture Actionable In a preclinical study, A-485 treatment inhibited proliferation in acute myeloid leukemia cell lines in culture (PMID: 28953875). 28953875
Unknown unknown multiple myeloma not applicable A-485 Preclinical - Cell culture Actionable In a preclinical study, A-485 treatment inhibited proliferation in multiple myeloma cell lines in culture (PMID: 28953875). 28953875