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)

Heffron, Timothy P.; Heald, Robert A.; Ndubaku, Chudi; Wei, BinQing; Augistin, Martin; Do, Steven; Edgar, Kyle; Eigenbrot, Charles; Friedman, Lori; Gancia, Emanuela; Jackson, Philip
S.; Jones, Graham; Kolesnikov, Aleksander; Lee, Leslie B.; Lesnick, John D.; Lewis, Cristina; McLean, Neville; Mörtl, Mario; Nonomiya, Jim; Pang, Jodie; Price, Steve; Prior, Wei Wei; Salphati, Laurent; Sideris, Steve; Staben, Steven T.; Steinbacher, Stefan; Tsui, Vickie; Wallin, Jeffrey; Sampath, Deepak; Olivero, Alan G.

doi:10.1021/acs.jmedchem.5b01483.s001

jm5b01483_si_001.pdf (556.85 kB)

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)

journal contribution

posted on 2016-02-22, 09:19 authored by Timothy P. Heffron, Robert A. Heald, Chudi Ndubaku, BinQing Wei, Martin Augistin, Steven Do, Kyle Edgar, Charles Eigenbrot, Lori Friedman, Emanuela Gancia, Philip S. Jackson, Graham Jones, Aleksander Kolesnikov, Leslie B. Lee, John D. Lesnick, Cristina Lewis, Neville McLean, Mario Mörtl, Jim Nonomiya, Jodie Pang, Steve Price, Wei Wei Prior, Laurent Salphati, Steve Sideris, Steven T. Staben, Stefan Steinbacher, Vickie Tsui, Jeffrey Wallin, Deepak Sampath, Alan G. Olivero

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).