Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.
Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.
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DOI：
10.1038/nature24028
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发表时间：
2017-10-05
期刊：
影响因子：
64.8
通讯作者：
Bromberg KD
中科院分区：
文献类型：
--
作者：
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
组蛋白乙酰转移酶（HAT）和组蛋白去乙酰化酶（HDAC）催化的蛋白质的动态可逆乙酰化是与多种疾病相关的基因转录的主要表观遗传调控机制。虽然HDAC抑制剂被批准用于治疗某些癌症，但药物样HAT抑制剂的开发进展滞后。HAT旁系同源物p300和CBP（p300/CBP）是许多细胞过程所必需的关键转录共激活因子，并且还涉及人类病理状况，包括癌症。目前的p300/CBP HAT结构域抑制剂包括天然产物、双底物类似物（Lys-CoA）和广泛使用的C646缺乏效力或选择性。在这里，我们描述了A-485，一种有效的，选择性的和药物样的p300/CBP催化抑制剂。我们展示了与p300催化活性位点结合的小分子的第一个高分辨率（1.95 μ m）共晶结构，并证明A-485是乙酰辅酶A竞争性的。A-485选择性抑制谱系特异性肿瘤类型的增殖，包括几种血液恶性肿瘤和雄激素受体阳性前列腺癌。A-485抑制雄激素敏感性和去势抵抗性前列腺癌中的雄激素受体转录程序，并抑制去势抵抗性异种移植模型中的肿瘤生长。这些结果证明了选择性靶向组蛋白乙酰转移酶的催化活性的可行性。
The dynamic and reversible acetylation of proteins catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) is a major epigenetic regulatory mechanism of gene transcription associated with multiple diseases. While HDAC inhibitors are approved to treat certain cancers, progress on the development of drug-like HAT inhibitors has lagged . The HAT paralogs p300 and CBP (p300/CBP) are key transcriptional co-activators essential for a multitude of cellular processes and also implicated in human pathological conditions, including cancer . Current p300/CBP HAT domain inhibitors including natural products, bi-substrate analogs (Lys-CoA) and the widely utilized C646 lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like p300/CBP catalytic inhibitor. We show the first high resolution (1.95Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 is acetyl-CoA competitive. A-485 selectively inhibited proliferation across lineage-specific tumor types, including several hematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen sensitive and castrate resistant prostate cancer and inhibited tumor growth in a castration resistant xenograft model. These results demonstrate the feasibility of selectively targeting the catalytic activity of histone acetyltransferases.
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影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
4.8
作者：
Hawksworth, D.;Ravindranath, L.;Petrovics, G.
通讯作者：
Petrovics, G.
影响因子：
14.8
作者：
Bromberg, Kenneth D.;Mitchell, Taylor R. H.;Pappano, William N.
通讯作者：
Pappano, William N.
影响因子：
7.3
作者：
Simon, Roman P.;Robaa, Dina;Jung, Manfred
通讯作者：
Jung, Manfred
影响因子：
28.2
作者：
Ogiwara, Hideaki;Sasaki, Mariko;Kohno, Takashi
通讯作者：
Kohno, Takashi