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Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases
ACS Medicinal Chemistry Letters ( IF 4.2 ) Pub Date : 2018-01-02 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00395
Michael R Michaelides 1 , Arthur Kluge 2 , Michael Patane 2 , John H Van Drie 2 , Ce Wang 3 , T Matthew Hansen 1 , Roberto M Risi 1 , Robert Mantei 1 , Carmen Hertel 2 , Kannan Karukurichi 2 , Alexandre Nesterov 2 , David McElligott 2 , Peter de Vries 2 , J William Langston 2 , Philip A Cole 2 , Ronen Marmorstein 2 , Hong Liu 1 , Loren Lasko 1 , Kenneth D Bromberg 1 , Albert Lai 1 , Edward A Kesicki 2
Affiliation  

p300 and its paralog CBP can acetylate histones and other proteins and have been implicated in a number of diseases characterized by aberrant gene activation, such as cancer. A novel, highly selective, orally bioavailable histone acetyltransferase (HAT) domain inhibitor has been identified through virtual ligand screening and subsequent optimization of a unique hydantoin screening hit. Conformational restraint in the form of a spirocyclization followed by substitution with a urea led to a significant improvement in potency. Replacement of the hydantoin moiety with an oxazolidinedione followed by fluoro substitution led to A-485, which exhibits potent cell activity, low clearance, and high oral bioavailability.

中文翻译:

发现螺恶唑烷二酮作为 p300/CBP 组蛋白乙酰转移酶的选择性口服生物可利用抑制剂

p300 及其旁系同源 CBP 可以乙酰化组蛋白和其他蛋白质,并与许多以异常基因激活为特征的疾病有关,例如癌症。通过虚拟配体筛选和随后对独特的乙内酰脲筛选命中进行优化,已鉴定出一种新型、高选择性、口服生物可利用的组蛋白乙酰转移酶 (HAT) 域抑制剂。螺环化形式的构象限制,然后用尿素取代导致效力的显着提高。用恶唑烷二酮替换乙内酰脲部分,然后进行氟取代导致A-485,其表现出有效的细胞活性、低清除率和高口服生物利用度。
更新日期:2018-01-02
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