发现螺环恶唑烷二酮类化合物作为p300/CBP组蛋白乙酰转移酶的选择性、口服生物可利用抑制剂。
Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases.
作者信息
Michaelides Michael R, Kluge Arthur, Patane Michael, Van Drie John H, Wang Ce, Hansen T Matthew, Risi Roberto M, Mantei Robert, Hertel Carmen, Karukurichi Kannan, Nesterov Alexandre, McElligott David, de Vries Peter, Langston J William, Cole Philip A, Marmorstein Ronen, Liu Hong, Lasko Loren, Bromberg Kenneth D, Lai Albert, Kesicki Edward A
机构信息
AbbVie, Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
Acylin Therapeutics, Inc., 1616 Eastlake Avenue E, Suite 200, Seattle, Washington 98012, United States.
出版信息
ACS Med Chem Lett. 2017 Dec 13;9(1):28-33. doi: 10.1021/acsmedchemlett.7b00395. eCollection 2018 Jan 11.
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 , which exhibits potent cell activity, low clearance, and high oral bioavailability.
p300及其旁系同源物CBP可使组蛋白和其他蛋白质发生乙酰化，并且与许多以基因异常激活为特征的疾病（如癌症）有关。通过虚拟配体筛选以及随后对一种独特的乙内酰脲筛选命中物进行优化，已鉴定出一种新型、高度选择性、口服生物可利用的组蛋白乙酰转移酶（HAT）结构域抑制剂。以螺环化形式进行构象限制，随后用脲进行取代，使效力得到显著提高。用恶唑烷二酮取代乙内酰脲部分，随后进行氟取代，得到了一种具有强大细胞活性、低清除率和高口服生物利用度的化合物。
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