Document Report Card

ID: ALA1773044

Journal: J Med Chem

Title: Potent, selective, and orally bioavailable inhibitors of mammalian target of rapamycin (mTOR) kinase based on a quaternary substituted dihydrofuropyrimidine.

Authors: Cohen F, Bergeron P, Blackwood E, Bowman KK, Chen H, Dipasquale AG, Epler JA, Koehler MF, Lau K, Lewis C, Liu L, Ly CQ, Malek S, Nonomiya J, Ortwine DF, Pei Z, Robarge KD, Sideris S, Trinh L, Truong T, Wu J, Zhao X, Lyssikatos JP.

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 K(i) < 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.

CiteXplore: 21495671

DOI: 10.1021/jm200215y