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PDBsum entry 5kcv
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Transferase/inhibitor
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PDB id
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5kcv
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References listed in PDB file
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Key reference
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Title
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Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-Phenyl-3h-Imidazo[4,5-B]pyridin-2-Yl)pyridin-2-Amine (arq 092): an orally bioavailable, Selective, And potent allosteric akt inhibitor.
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Authors
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J.M.Lapierre,
S.Eathiraj,
D.Vensel,
Y.Liu,
C.O.Bull,
S.Cornell-Kennon,
S.Iimura,
E.W.Kelleher,
D.E.Kizer,
S.Koerner,
S.Makhija,
A.Matsuda,
M.Moussa,
N.Namdev,
R.E.Savage,
J.Szwaya,
E.Volckova,
N.Westlund,
H.Wu,
B.Schwartz.
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Ref.
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J Med Chem, 2016,
59,
6455-6469.
[DOI no: ]
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PubMed id
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Abstract
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The work in this paper describes the optimization of the
3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine chemical series as
potent, selective allosteric inhibitors of AKT kinases, leading to the discovery
of ARQ 092 (21a). The cocrystal structure of compound 21a bound to full-length
AKT1 confirmed the allosteric mode of inhibition of this chemical class and the
role of the cyclobutylamine moiety. Compound 21a demonstrated high enzymatic
potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of
AKT activation and the phosphorylation of the downstream target PRAS40. Compound
21a also served as a potent inhibitor of the AKT1-E17K mutant protein and
inhibited tumor growth in a human xenograft mouse model of endometrial
adenocarcinoma.
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