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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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PDB id:
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| Name: |
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Transferase/inhibitor
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Title:
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Crystal structure of allosteric inhibitor, arq 092, in complex with autoinhibited form of akt1
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Structure:
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Rac-alpha serine/threonine-protein kinase. Chain: a. Synonym: protein kinase b,pkb,protein kinase b alpha,pkb alpha,proto- oncogenE C-akt,rac-pk-alpha. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: akt1, pkb, rac. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9
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Resolution:
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2.70Å
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R-factor:
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0.213
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R-free:
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0.269
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Authors:
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S.Eathiraj
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Key ref:
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J.M.Lapierre
et al.
(2016).
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.
J Med Chem,
59,
6455-6469.
PubMed id:
DOI:
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Date:
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07-Jun-16
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Release date:
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29-Jun-16
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PROCHECK
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Headers
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References
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P31749
(AKT1_HUMAN) -
RAC-alpha serine/threonine-protein kinase from Homo sapiens
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Seq:
Struc:
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480 a.a.
353 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.7.11.1
- non-specific serine/threonine protein kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
59:6455-6469
(2016)
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PubMed id:
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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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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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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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