当前位置: X-MOL 学术ACS Med. Chem. Lett. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
New Potent DOT1L Inhibitors for in Vivo Evaluation in Mouse.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-12-04 , DOI: 10.1021/acsmedchemlett.9b00452
Frédéric Stauffer 1 , Andreas Weiss 1 , Clemens Scheufler 1 , Henrik Möbitz 1 , Christian Ragot 1 , Kim S Beyer 1 , Keith Calkins 1 , Daniel Guthy 1 , Michael Kiffe 1 , Bernard Van Eerdenbrugh 1 , Ralph Tiedt 1 , Christoph Gaul 1
Affiliation  

In MLL-rearranged cancer cells, disruptor of telomeric silencing 1-like protein (DOT1L) is aberrantly recruited to ectopic loci leading to local hypermethylation of H3K79 and consequently misexpression of leukemogenic genes. A structure-guided optimization of a HTS hit led to the discovery of DOT1L inhibitors with subnanomolar potency, allowing testing of the therapeutic principle of DOT1L inhibition in a preclinical mouse tumor xenograft model. Compounds displaying good exposure in mouse and nanomolar inhibition of target gene expression in cells were obtained and tested in vivo.

中文翻译:

用于小鼠体内评估的新型有效DOT1L抑制剂。

在MLL重排的癌细胞中,端粒沉默1样蛋白(DOT1L)的破坏者异常地募集到异位基因位点,导致H3K79局部过度甲基化,从而致白血病基因的错误表达。HTS命中的结构指导优化导致发现了具有亚纳摩尔效价的DOT1L抑制剂,从而可以在临床前小鼠肿瘤异种移植模型中测试DOT1L抑制的治疗原理。获得并在体内测试了在小鼠中表现出良好的暴露以及在细胞中纳摩尔抑制靶基因表达的化合物。
更新日期:2019-12-04
down
wechat
bug