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PDBsum entry 6mdc
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Hydrolase/hydrolase inhibitor
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PDB id
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6mdc
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PDB id:
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| Name: |
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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 1 shp389
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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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2.14Å
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R-factor:
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0.194
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R-free:
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0.239
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Authors:
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M.Fodor,T.Stams
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Key ref:
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J.T.Bagdanoff
et al.
(2019).
Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors.
J Med Chem,
62,
1781-1792.
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.
483 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
62:1781-1792
(2019)
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PubMed id:
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Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors.
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J.T.Bagdanoff,
Z.Chen,
M.Acker,
Y.N.Chen,
H.Chan,
M.Dore,
B.Firestone,
M.Fodor,
J.Fortanet,
M.Hentemann,
M.Kato,
R.Koenig,
L.R.LaBonte,
S.Liu,
M.Mohseni,
R.Ntaganda,
P.Sarver,
T.Smith,
M.Sendzik,
T.Stams,
S.Spence,
C.Towler,
H.Wang,
P.Wang,
S.L.Williams,
M.J.LaMarche.
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ABSTRACT
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SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated
protein kinase (MAPK) pathway controlling cell growth, differentiation, and
oncogenic transformation. SHP2 also participates in the programed cell death
pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of
SHP2 has been widely investigated, including in our previous reports describing
SHP099 (2), which binds to a tunnel-like allosteric binding site. To broaden our
approach to allosteric inhibition of SHP2, we conducted additional hit finding,
evaluation, and structure-based scaffold morphing. These studies, reported here
in the first of two papers, led to the identification of multiple 5,6-fused
bicyclic scaffolds that bind to the same allosteric tunnel as 2. We demonstrate
the structural diversity permitted by the tunnel pharmacophore and culminated in
the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that modulate MAPK
signaling in vivo. These studies also served as the basis for further scaffold
morphing and optimization, detailed in the following manuscript.
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Links
