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PDBsum entry 7jvm
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Hydrolase/hydrolase inhibitor
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PDB id
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7jvm
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References listed in PDB file
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Key reference
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Title
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Identification of tno155, An allosteric shp2 inhibitor for the treatment of cancer.
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Authors
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M.J.Lamarche,
M.Acker,
A.Argintaru,
D.Bauer,
J.Boisclair,
H.Chan,
C.H.Chen,
Y.N.Chen,
Z.Chen,
Z.Deng,
M.Dore,
D.Dunstan,
J.Fan,
P.Fekkes,
B.Firestone,
M.Fodor,
J.Garcia-Fortanet,
P.D.Fortin,
C.Fridrich,
J.Giraldes,
M.Glick,
D.Grunenfelder,
H.X.Hao,
M.Hentemann,
S.Ho,
A.Jouk,
Z.B.Kang,
R.Karki,
M.Kato,
N.Keen,
R.Koenig,
L.R.Labonte,
J.Larrow,
G.Liu,
S.Liu,
D.Majumdar,
S.Mathieu,
M.J.Meyer,
M.Mohseni,
R.Ntaganda,
M.Palermo,
L.Perez,
M.Pu,
T.Ramsey,
J.Reilly,
P.Sarver,
W.R.Sellers,
M.Sendzik,
M.D.Shultz,
J.Slisz,
K.Slocum,
T.Smith,
S.Spence,
T.Stams,
C.Straub,
V.Tamez,
B.B.Toure,
C.Towler,
P.Wang,
H.Wang,
S.L.Williams,
F.Yang,
B.Yu,
J.H.Zhang,
S.Zhu.
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Ref.
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J Med Chem, 2020,
63,
13578-13594.
[DOI no: ]
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PubMed id
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Abstract
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SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11
gene and is involved in cell growth and differentiation via the MAPK signaling
pathway. SHP2 also plays an important role in the programed cell death pathway
(PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator,
controlling SHP2 activity is of high therapeutic interest. As part of our
comprehensive program targeting SHP2, we identified multiple allosteric binding
modes of inhibition and optimized numerous chemical scaffolds in parallel. In
this drug annotation report, we detail the identification and optimization of
the pyrazine class of allosteric SHP2 inhibitors. Structure and property based
drug design enabled the identification of protein-ligand interactions, potent
cellular inhibition, control of physicochemical, pharmaceutical and selectivity
properties, and potent in vivo antitumor activity. These studies
culminated in the discovery of TNO155,
(3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine
(1), a highly potent, selective, orally efficacious, and first-in-class
SHP2 inhibitor currently in clinical trials for cancer.
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