2. Academic Validation
  3. Discovery of 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-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity

Discovery of 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-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity

  • J Med Chem. 2013 Jun 13;56(11):4597-610. doi: 10.1021/jm4003632.
Chudi O Ndubaku 1,  Timothy P Heffron,  Steven T Staben,  Matthew Baumgardner,  Nicole Blaquiere,  Erin Bradley,  Richard 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,  Jeffery J Wallin,  Lan Wang,  BinQing Wei,  Deepak Sampath,  Alan G Olivero
Affiliations

Affiliation

  • 1 Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. chudin@gene.com
PMID: 23662903 DOI: 10.1021/jm4003632
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13898
    99.75%, PIK3CA 抑制剂
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