Determination of Pt–DNA adducts and the sub-cellular distribution of Pt in human cancer cell lines and the leukocytes of cancer patients, following mono- or combination treatments, by inductively-coupled plasma mass spectrometry

This is the author’s version of a work that was accepted for publication in the International Journal of Mass Spectrometry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published at: http://dx.doi.org/10.1016/j.ijms.2010.11.01

Discovery of 3‑(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl‑3<i>H</i>‑imidazo[4,5‑<i>b</i>]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor

The work in this paper describes the optimization of the 3-(3-phenyl-3<i>H</i>-imidazo­[4,5-<i>b</i>]­pyridin-2-yl)­pyridin-2-amine chemical series as potent, selective allosteric inhibitors of AKT kinases, leading to the discovery of ARQ 092 (<b>21a</b>). The cocrystal structure of compound <b>21a</b> bound to full-length AKT1 confirmed the allosteric mode of inhibition of this chemical class and the role of the cyclobutylamine moiety. Compound <b>21a</b> demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40. Compound <b>21a</b> also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma