학술논문
Potent, Selective, and Orally Bioavailable Inhibitors of Mammalian Target of Rapamycin (mTOR) Kinase Based on a Quaternary Substituted Dihydrofuropyrimidine
Document Type
Article
Author
Cohen, Frederick; Bergeron, Philippe; Blackwood, Elizabeth; Bowman, Krista K.; Chen, Huifen; DiPasquale, Antonio G.; Epler, Jennifer A.; Koehler, Michael F. T.; Lau, Kevin; Lewis, Cristina; Liu, Lichuan; Ly, Cuong Q.; Malek, Shiva; Nonomiya, Jim; Ortwine, Daniel F.; Pei, Zhonghua; Robarge, Kirk D.; Sideris, Steve; Trinh, Lan; Truong, Tom; Wu, Jiansheng; Zhao, Xianrui; Lyssikatos, Joseph P.
Source
Journal of Medicinal Chemistry; 20240101, Issue: Preprints
Subject
Language
ISSN
00222623; 15204804
Abstract
A series of inhibitors of mTOR kinase based on a quaternary-substituted dihydrofuropyrimidine was designed and synthesized. The most potent compounds in this series inhibited mTOR kinase with Ki< 1.0 nM and were highly (>100×) selective for mTOR over the closely related PI3 kinases. Compounds in this series showed inhibition of the pathway and antiproliferative activity in cell-based assays. Furthermore, these compounds had excellent mouse PK, and showed a robust PK−PD relationship in a mouse model of cancer.