2. Academic Validation
  3. The Rational Design of Selective Benzoxazepin Inhibitors of the α-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326)

The Rational Design of Selective Benzoxazepin Inhibitors of the α-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326)

  • J Med Chem. 2016 Feb 11;59(3):985-1002. doi: 10.1021/acs.jmedchem.5b01483.
Timothy P Heffron 1,  Robert A Heald 2,  Chudi Ndubaku 1,  BinQing Wei 1,  Martin Augistin 3,  Steven Do 1,  Kyle Edgar 1,  Charles Eigenbrot 1,  Lori Friedman 1,  Emanuela Gancia 2,  Philip S Jackson 2,  Graham Jones 2,  Aleksander Kolesnikov 1,  Leslie B Lee 1,  John D Lesnick 1,  Cristina Lewis 1,  Neville McLean 2,  Mario Mörtl 3,  Jim Nonomiya 1,  Jodie Pang 1,  Steve Price 2,  Wei Wei Prior 1,  Laurent Salphati 1,  Steve Sideris 1,  Steven T Staben 1,  Stefan Steinbacher 3,  Vickie Tsui 1,  Jeffrey Wallin 1,  Deepak Sampath 1,  Alan G Olivero 1
Affiliations

Affiliations

  • 1 Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
  • 2 Argenta , Early Discovery Charles River, 7-9 Spire Green Centre, Flex Meadow, Harlow, EssexCM19 5TR, United Kingdom.
  • 3 Proteros Biostructures GmbH , Bunsenstr. 7aD, 82152 Martinsried, Germany.
PMID: 26741947 DOI: 10.1021/acs.jmedchem.5b01483
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).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101272
    99.92%, PI3Kα抑制剂
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