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.

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

机译：发现针对谱系特异性肿瘤的选择性催化p300 / CBP抑制剂

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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(1) 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(2). 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(3)). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products(4), bi-substrate analogues(5) and the widely used small molecule C646(6,7), 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 angstrom) 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.

机译：组蛋白乙酰基转移酶（HATs）和组蛋白脱乙酰基酶（HDACs）催化的蛋白质动态和可逆乙酰化作用是基因转录的主要表观遗传调控机制（1），与多种疾病有关。组蛋白脱乙酰基酶抑制剂目前已被批准用于治疗某些癌症，但在药物样组蛋白乙酰转移酶抑制剂的开发方面却落后了（2）。组蛋白乙酰基转移酶旁系同源物p300和CREB结合蛋白（CBP）是关键的转录共激活子，对于许多细胞过程都是必不可少的，并且也与人类病理状况有关（包括癌症（3））。目前p300和CBP组蛋白乙酰转移酶结构域的抑制剂，包括天然产物（4），双底物类似物（5）和广泛使用的小分子C646（6,7），均缺乏效价或选择性。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和CBP催化抑制剂。我们目前的高分辨率（1.95埃）小分子与p300的催化活性位点结合的共晶体结构，并证明A-485与乙酰辅酶A（乙酰辅酶A）竞争。 A-485在特定谱系的肿瘤类型（包括几种血液系统恶性肿瘤和雄激素受体阳性的前列腺癌）中选择性抑制增殖。 A-485在雄激素敏感和去势抵抗性前列腺癌中均抑制雄激素受体转录程序，并在去势抵抗异种移植模型中抑制肿瘤生长。这些结果证明了使用小分子抑制剂选择性靶向组蛋白乙酰转移酶的催化活性的可行性，这可以为转录激活因子驱动的恶性肿瘤和疾病提供有效的治疗方法。

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《Nature》 |2017年第7674期|128-132|共5页
作者
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.;
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AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA|eFFECTOR Therapeut, 11180 Roselle St,Suite A, San Diego, CA 92121 USA;

Petra Pharma Corp, 430 E 29th St,Suite 435, New York, NY 10016 USA;

Faraday Pharmaceut, 1616 Eastlake Ave E, Seattle, WA 98102 USA;

Univ Copenhagen, Fac Hlth & Med Sci, Nordisk Fdn Ctr Prot Res, Dept Prote, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark;

Univ Copenhagen, Fac Hlth & Med Sci, Nordisk Fdn Ctr Prot Res, Dept Prote, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark;

Cascadian Therapeut Inc, 2601 Fourth Ave,Suite 500, Seattle, WA 98121 USA;

Van Drie Res, 109 Millpond, Andover, MA 01845 USA;

Accelerator Corp, 430 East 29th St, New York, NY 10106 USA;

Petra Pharma Corp, 430 E 29th St,Suite 435, New York, NY 10016 USA;

Univ Penn, Perelman Sch Med, 421 Curie Blvd, Philadelphia, PA 19104 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

Johns Hopkins Univ, 725 N Wolfe St, Baltimore, MD 21205 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

AbbVie, Discovery Global Pharmaceut Res & Dev, 1 North Waukegan Rd, N Chicago, IL 60064 USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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1. Targeting Lineage-specific MITF Pathway in Human Melanoma Cell Lines by A-485, the Selective Small-molecule Inhibitor of p300/CBP [J] . Wang Rui, He Yupeng, Robinson Valerie, Molecular cancer therapeutics . 2018,第12期

机译：通过A-485靶向人黑色素瘤细胞系中的谱系特异性MITF途径，P300 / CBP的选择性小分子抑制剂
2. Another One (of the “Undruggable” Targets) Bites the Dust: Discovery of a Potent and Selective Inhibitor of the Histone Acetyl Transferase p300/CBP [J] . Thomas Kodadek Biochemistry . 2018,第6期

机译：另一个（“不可申请的”目标）咬尘埃：发现组蛋白乙酰转移酶P300 / CBP的有效和选择性抑制剂
3. Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors [J] . Yang Yaxi, Zhang Rukang, Li Zhaojun, Journal of Medicinal Chemistry . 2020,第3期

机译：发现高效，选择性和口服有效的P300 / CBP组氨基乙酰转移酶抑制剂
4. Fc Fusion Affimer? Biotherapeutic Targeting PD-L1 Inhibits Tumour Growth in Mouse [C] . Fran Mullen, E. Adam, E. Jenkins, Protein Engineering Summit. . 2018

机译：FC Fusion AINIMER？生物治疗靶向PD-L1抑制小鼠的肿瘤生长
5. Histone acetyltransferase p300/CBP as a functionally significant target in melanoma. [D] . Yan, Gai. 2012

机译：组蛋白乙酰转移酶p300 / CBP是黑色素瘤中功能上重要的靶标。
6. Discovery of a potent catalytic p300/CBP inhibitor that targets lineage-specific tumors [O] . Loren M. Lasko, Clarissa G. Jakob, Rohinton P. Edalji, -1

机译：发现了针对谱系特异性肿瘤的有效催化性p300 / CBP抑制剂
7. Author Correction: Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours [O] . Loren M. Lasko, Clarissa G. Jakob, Rohinton P. Edalji, 2018

机译：作者校正：发现靶向谱系特异性肿瘤的选择性催化P300 / CBP抑制剂

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

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