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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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References listed in PDB file
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Key reference
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Title
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Optimization of fused bicyclic allosteric shp2 inhibitors.
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Authors
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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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Ref.
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J Med Chem, 2019,
62,
1781-1792.
[DOI no: ]
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PubMed id
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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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