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
  • 1. Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. [email protected]
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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13898
    Taselisib
    99.75%, PIK3CA Inhibitor
    target: PI3K
    Research Areas: Cancer