학술논문
Discoveryof 2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide(GDC-0032): A β-Sparing Phosphoinositide 3-KinaseInhibitor with High Unbound Exposure and Robust in Vivo AntitumorActivity
Document Type
Article
Author
Ndubaku, Chudi O.; Heffron, Timothy P.; Staben, Steven T.; Baumgardner, Matthew; Blaquiere, Nicole; Bradley, Erin; Bull, Richard; Do, Steven; Dotson, Jennafer; Dudley, Danette; Edgar, Kyle A.; Friedman, Lori S.; Goldsmith, Richard; Heald, Robert A.; Kolesnikov, Aleksandr; Lee, Leslie; Lewis, Cristina; Nannini, Michelle; Nonomiya, Jim; Pang, Jodie
Source
Subject
*AMIDES
*PHOSPHOINOSITIDE-dependent kinase-1
*CHEMICAL inhibitors
*CELLULAR signal transduction
*PROTEIN kinase B
*MTOR protein
*ANTINEOPLASTIC agents
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Language
ISSN
0022-2623
Abstract
Dysfunctional signalingthrough the phosphoinositide 3-kinase (PI3K)/AKT/mTORpathway leads to uncontrolled tumor proliferation. In the course ofthe discovery of novel benzoxepin PI3K inhibitors, we observed a strongdependency of in vivo antitumor activity on the free-drug exposure.By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepincompounds that showed improved unbound drug exposure and effectivelysuppressed growth of tumors in a mouse xenograft model at low drugdose levels. One of these compounds, GDC-0032 (11l),was progressed to clinical trials and is currently under phase I evaluationas a potential treatment for human malignancies. [ABSTRACT FROM AUTHOR]