发现螺噁二嗪酮类化合物作为选择性、口服生物利用度的 p300/CBP 组蛋白乙酰转移酶抑制剂。
Discovery of spirohydantoins as selective, orally bioavailable inhibitors of p300/CBP histone acetyltransferases.
机构信息
Abbvie, Inc. 1 North Waukegan Road, North Chicago, IL-60064, United States.
Abbvie, Inc. 1 North Waukegan Road, North Chicago, IL-60064, United States.
出版信息
Bioorg Med Chem Lett. 2021 May 1;39:127854. doi: 10.1016/j.bmcl.2021.127854. Epub 2021 Feb 23.
Abstract
p300 and CREB-binding protein (CBP) are essential for a multitude of cellular processes. Dysregulation of p300/CBP histone acetyltransferase activity is linked to a broad spectrum of human diseases including cancers. A novel drug-like spirohydantoin (21) has been discovered as a selective orally bioavailable inhibitor of p300/CBP histone acetyltransferase. Lead compound 21 is more potent than the first-in-class lead A-485 in both enzymatic and cellular assays and lacks the off-target inhibition of dopamine and serotonin transporters, that was observed with A-485.
摘要
p300 和 CREB 结合蛋白（CBP）对于多种细胞过程至关重要。p300/CBP 组蛋白乙酰转移酶活性的失调与包括癌症在内的广泛的人类疾病有关。一种新型的类药螺环缩酮（21）已被发现是一种选择性的口服生物可利用的 p300/CBP 组蛋白乙酰转移酶抑制剂。与 A-485 相比，先导化合物 21 在酶和细胞测定中均具有更高的活性，并且缺乏 A-485 观察到的对多巴胺和 5-羟色胺转运体的非靶标抑制作用。
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ACS Med Chem Lett. 2020 Apr 23;11(6):1324-1329. doi: 10.1021/acsmedchemlett.0c00155. eCollection 2020 Jun 11.
2
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3
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4
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5
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6
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10
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Curr Opin Struct Biol. 2008 Dec;18(6):741-7. doi: 10.1016/j.sbi.2008.09.004. Epub 2008 Oct 27.
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