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PDBsum entry 6mdb
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Hydrolase/hydrolase inhibitor
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PDB id
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6mdb
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PDB id:
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Hydrolase/hydrolase inhibitor
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Title:
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Non-receptor protein tyrosine phosphatase shp2 in complex with allosteric inhibitor pyrazolo-pyrimidinone 5
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Structure:
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Tyrosine-protein phosphatase non-receptor type 11. Chain: a, b. Synonym: protein-tyrosine phosphatase 1d,ptp-1d,protein-tyrosine phosphatase 2c,ptp-2c,sh-ptp2,shp2,sh-ptp3. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn11, ptp2c, shptp2. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.34Å
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R-factor:
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0.175
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R-free:
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0.236
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Authors:
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M.Fodor,T.Stams
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Key ref:
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P.Sarver
et al.
(2019).
6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors.
J Med Chem,
62,
1793-1802.
PubMed id:
DOI:
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Date:
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04-Sep-18
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Release date:
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13-Feb-19
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PROCHECK
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Headers
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References
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Q06124
(PTN11_HUMAN) -
Tyrosine-protein phosphatase non-receptor type 11 from Homo sapiens
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Seq:
Struc:
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593 a.a.
487 a.a.
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Enzyme class:
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E.C.3.1.3.48
- protein-tyrosine-phosphatase.
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Reaction:
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O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate
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O-phospho-L-tyrosyl-[protein]
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+
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H2O
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=
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L-tyrosyl-[protein]
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+
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phosphate
Bound ligand (Het Group name = )
corresponds exactly
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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
62:1793-1802
(2019)
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PubMed id:
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6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors.
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P.Sarver,
M.Acker,
J.T.Bagdanoff,
Z.Chen,
Y.N.Chen,
H.Chan,
B.Firestone,
M.Fodor,
J.Fortanet,
H.Hao,
M.Hentemann,
M.Kato,
R.Koenig,
L.R.LaBonte,
G.Liu,
S.Liu,
C.Liu,
E.McNeill,
M.Mohseni,
M.Sendzik,
T.Stams,
S.Spence,
V.Tamez,
R.Tichkule,
C.Towler,
H.Wang,
P.Wang,
S.L.Williams,
B.Yu,
M.J.LaMarche.
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ABSTRACT
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Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as
well as a potential immune modulator because of its role in the programmed cell
death PD-L1/PD-1 pathway. In the preceding manuscript, we described the
optimization of a fused, bicyclic screening hit for potency, selectivity, and
physicochemical properties in order to further expand the chemical diversity of
allosteric SHP2 inhibitors. In this manuscript, we describe the further
expansion of our approach, morphing the fused, bicyclic system into a novel
monocyclic pyrimidinone scaffold through our understanding of SAR and use of
structure-based design. These studies led to the identification of SHP394 (1),
an orally efficacious inhibitor of SHP2, with high lipophilic efficiency,
improved potency, and enhanced pharmacokinetic properties. We also report other
pyrimidinone analogues with favorable pharmacokinetic and potency profiles.
Overall, this work improves upon our previously described allosteric inhibitors
and exemplifies and extends the range of permissible chemical templates that
inhibit SHP2 via the allosteric mechanism.
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