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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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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 tno155
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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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2.17Å
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R-factor:
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0.194
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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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M.J.LaMarche
et al.
(2020).
Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.
J Med Chem,
63,
13578-13594.
PubMed id:
DOI:
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Date:
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21-Aug-20
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Release date:
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23-Sep-20
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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.
486 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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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
63:13578-13594
(2020)
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PubMed id:
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Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.
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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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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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