Portal de Periódicos da CAPES

Discovery of 2-{3-[2-(1-Isopropyl-3-methyl-1 H -1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d ][1,4]oxazepin-9-yl]-1 H -pyrazol-1-yl}-2-methylpropanamide (GDC-0032): A β-Sparing Phosphoinositide 3-Kinase Inhibitor with High Unbound Exposure and Robust in Vivo Antitumor Activity

2013; American Chemical Society; Volume: 56; Issue: 11 Linguagem: Inglês

10.1021/jm4003632

1520-4804

Chudi Ndubaku, Timothy P. Heffron, Steven T. Staben, Matthew Baumgardner, Nicole Blaquière, Erin K. Bradley, Richard J. Bull, Steven Do, Jennafer Dotson, Danette Dudley, Kyle A. Edgar, Lori S. Friedman, Richard Goldsmith, Robert A. Heald, Aleksandr Kolesnikov, Leslie Lee, Cristina Lewis, Michelle Nannini, Jim Nonomiya, Jodie Pang, Steve Price, Wei Wei Prior, Laurent Salphati, Steve Sideris, Jeffrey J. Wallin, Lan Wang, BinQing Wei, Deepak Sampath, Alan G. Olivero,

Biochemical and Molecular Research

Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies.