小分子ENL YEATS抑制剂的先导优化以促进研究：TDI-11055的发现。
Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable Studies: Discovery of TDI-11055.
作者信息
Michino Mayako, Khan Tanweer A, Miller Michael W, Fukase Yoshiyuki, Vendome Jeremie, Adura Carolina, Glickman J Fraser, Liu Yiman, Wan Liling, Allis C David, Stamford Andrew W, Meinke Peter T, Renzetti Louis M, Kargman Stacia, Liverton Nigel J, Huggins David J
机构信息
Sanders Tri-Institutional Therapeutics Discovery Institute, 1230 York Ave, Box 122, New York, New York 10065, United States.
Schrödinger, Inc., 1540 Broadway, 24th Floor, New York, New York 10036, United States.
出版信息
ACS Med Chem Lett. 2024 Mar 12;15(4):524-532. doi: 10.1021/acsmedchemlett.4c00016. eCollection 2024 Apr 11.
Eleven-nineteen leukemia (ENL) is an epigenetic reader protein that drives oncogenic transcriptional programs in acute myeloid leukemia (AML). AML is one of the deadliest hematopoietic malignancies, with an overall 5-year survival rate of 27%. The epigenetic reader activity of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl marks on histone tails and colocalizes with promoters of actively transcribed genes that are essential for leukemia. Prior to the discovery of , existing inhibitors of ENL YEATS showed potency, but had not shown efficacy in animal models. During the course of the medicinal chemistry campaign described here, we identified ENL YEATS inhibitor that has an improved pharmacokinetic profile and is appropriate for evaluation of the ENL YEATS inhibition mechanism in AML.
11-19白血病（ENL）是一种表观遗传阅读蛋白，可驱动急性髓性白血病（AML）中的致癌转录程序。AML是最致命的血液系统恶性肿瘤之一，总体5年生存率为27%。ENL的表观遗传阅读活性由其YEATS结构域介导，该结构域与组蛋白尾部的乙酰基和巴豆酰基标记结合，并与白血病必需的活跃转录基因的启动子共定位。在发现[具体内容缺失]之前，现有的ENL YEATS抑制剂显示出[具体效力缺失]，但在动物模型中未显示出疗效。在此描述的药物化学研究过程中，我们鉴定出一种ENL YEATS抑制剂，其具有改善的药代动力学特征，适用于评估AML中ENL YEATS的抑制机制。
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