铑（II）邻近标记鉴定出信号转导和转录激活因子3（STAT3）上的一个新靶点，该靶点可用于具有强效抗白血病活性的抑制剂。
Rhodium(II) Proximity-Labeling Identifies a Novel Target Site on STAT3 for Inhibitors with Potent Anti-Leukemia Activity.
作者信息
Minus Matthew B, Liu Wei, Vohidov Farrukh, Kasembeli Moses M, Long Xin, Krueger Michael J, Stevens Alexandra, Kolosov Mikhail I, Tweardy David J, Sison Edward Allan R, Redell Michele S, Ball Zachary T
机构信息
Department of Chemistry, Rice University, Houston, TX 77005 (USA).
Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX 77030 (USA).
出版信息
Angew Chem Int Ed Engl. 2015 Oct 26;54(44):13085-9. doi: 10.1002/anie.201506889. Epub 2015 Sep 7.
Abstract
Nearly 40 % of children with acute myeloid leukemia (AML) suffer relapse arising from chemoresistance, often involving upregulation of the oncoprotein STAT3 (signal transducer and activator of transcription 3). Herein, rhodium(II)-catalyzed, proximity-driven modification identifies the STAT3 coiled-coil domain (CCD) as a novel ligand-binding site, and we describe a new naphthalene sulfonamide inhibitor that targets the CCD, blocks STAT3 function, and halts its disease-promoting effects in vitro, in tumor growth models, and in a leukemia mouse model, validating this new therapeutic target for resistant AML.
摘要
近40%的急性髓系白血病（AML）患儿会因化疗耐药而复发，这通常涉及癌蛋白信号转导和转录激活因子3（STAT3）的上调。在此，铑（II）催化的邻近驱动修饰确定STAT3卷曲螺旋结构域（CCD）为一个新的配体结合位点，并且我们描述了一种靶向CCD的新型萘磺酰胺抑制剂，该抑制剂可阻断STAT3功能，并在体外、肿瘤生长模型以及白血病小鼠模型中阻止其促疾病作用，从而验证了这一针对耐药AML的新治疗靶点。
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