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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J Med Chem. 2020 Feb 13;63(3):1337-1360. doi: 10.1021/acs.jmedchem.9b01721. Epub 2020 Jan 28.
3
Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases.
ACS Med Chem Lett. 2017 Dec 13;9(1):28-33. doi: 10.1021/acsmedchemlett.7b00395. eCollection 2018 Jan 11.
4
Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.
Nature. 2017 Oct 5;550(7674):128-132. doi: 10.1038/nature24028. Epub 2017 Sep 27.
5
Super-enhancers in the control of cell identity and disease.
Cell. 2013 Nov 7;155(4):934-47. doi: 10.1016/j.cell.2013.09.053. Epub 2013 Oct 10.
6
Transcriptional/epigenetic regulator CBP/p300 in tumorigenesis: structural and functional versatility in target recognition.
Cell Mol Life Sci. 2013 Nov;70(21):3989-4008. doi: 10.1007/s00018-012-1254-4. Epub 2013 Jan 11.
7
Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation.
EMBO J. 2011 Jan 19;30(2):249-62. doi: 10.1038/emboj.2010.318. Epub 2010 Dec 3.
8
Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases.
Epigenetics. 2010 Jan 1;5(1):9-15. doi: 10.4161/epi.5.1.10449. Epub 2010 Jan 27.
9
The many roles of histone deacetylases in development and physiology: implications for disease and therapy.
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10
Structure and chemistry of the p300/CBP and Rtt109 histone acetyltransferases: implications for histone acetyltransferase evolution and function.
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