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PDBsum entry 5dxh
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Transferase/transferase inhibitor
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PDB id
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5dxh
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References listed in PDB file
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Key reference
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Title
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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).
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Authors
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T.P.Heffron,
R.A.Heald,
C.Ndubaku,
B.Wei,
M.Augistin,
S.Do,
K.Edgar,
C.Eigenbrot,
L.Friedman,
E.Gancia,
P.S.Jackson,
G.Jones,
A.Kolesnikov,
L.B.Lee,
J.D.Lesnick,
C.Lewis,
N.Mclean,
M.Mörtl,
J.Nonomiya,
J.Pang,
S.Price,
W.W.Prior,
L.Salphati,
S.Sideris,
S.T.Staben,
S.Steinbacher,
V.Tsui,
J.Wallin,
D.Sampath,
A.G.Olivero.
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Ref.
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J Med Chem, 2016,
59,
985.
[DOI no: ]
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PubMed id
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Abstract
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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).
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