The Benzoxazepin Inhibitors of the α-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of GDC-0326)
† Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
‡ Argenta, Early Discovery Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, EssexCM19 5TR, United Kingdom
§ Proteros Biostructures GmbH, Bunsenstr. 7aD, 82152 Martinsried, Germany
J. Med. Chem., 2016, 59 (3), pp 985–1002
DOI: 10.1021/acs.jmedchem.5b01483
Publication Date (Web): January 7, 2016
Copyright © 2016 American Chemical Society
Abstract
Inhibitors of the class I phosphoinositide 3-kinase (PI3K) isoform PI3Kα have received substantial attention for their potential use in cancer therapy. Despite the particular attraction of targeting PI3Kα, achieving selectivity for the inhibition of this isoform has proved challenging. Herein we report the discovery of inhibitors of PI3Kα that have selectivity over the other class I isoforms and all other kinases tested. In GDC-0032 (3, taselisib), we previously minimized inhibition of PI3Kβ relative to the other class I insoforms. Subsequently, we extended our efforts to identify PI3Kα-specific inhibitors using PI3Kα crystal structures to inform the design of benzoxazepin inhibitors with selectivity for PI3Kα through interactions with a nonconserved residue. Several molecules selective for PI3Kα relative to the other class I isoforms, as well as other kinases, were identified. Optimization of properties related to drug metabolism then culminated in the identification of the clinical candidate GDC-0326 (4).
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.5b01483.
- A kinase selectivity panel for 4, a figure explaining the Link and Grow strategies used to design PI3Kα specific inhibitors, crystal structure metrics as well as a depiction of a crystal structure of a benzoxepin bound to PI3Kγ (PDB 3R7R) where residues are labeled to highlight differences between PI3Kα and the other isoforms within the active site (PDF)
Triazole Structure is Simple & Easly accesible from corresponding Carbonyl (C=O) functinality.
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