 |
PDBsum entry 5ehr
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
5ehr
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Allosteric inhibition of shp2 phosphatase inhibits cancers driven by receptor tyrosine kinases.
|
|
|
Authors
|
|
Y.N.Chen,
M.J.Lamarche,
H.M.Chan,
P.Fekkes,
J.Garcia-Fortanet,
M.G.Acker,
B.Antonakos,
C.H.Chen,
Z.Chen,
V.G.Cooke,
J.R.Dobson,
Z.Deng,
F.Fei,
B.Firestone,
M.Fodor,
C.Fridrich,
H.Gao,
D.Grunenfelder,
H.X.Hao,
J.Jacob,
S.Ho,
K.Hsiao,
Z.B.Kang,
R.Karki,
M.Kato,
J.Larrow,
L.R.La bonte,
F.Lenoir,
G.Liu,
S.Liu,
D.Majumdar,
M.J.Meyer,
M.Palermo,
L.Perez,
M.Pu,
E.Price,
C.Quinn,
S.Shakya,
M.D.Shultz,
J.Slisz,
K.Venkatesan,
P.Wang,
M.Warmuth,
S.Williams,
G.Yang,
J.Yuan,
J.H.Zhang,
P.Zhu,
T.Ramsey,
N.J.Keen,
W.R.Sellers,
T.Stams,
P.D.Fortin.
|
|
|
Ref.
|
|
Nature, 2016,
535,
148-152.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an
important role in signal transduction downstream of growth factor receptor
signalling and was the first reported oncogenic tyrosine phosphatase. Activating
mutations of SHP2 have been associated with developmental pathologies such as
Noonan syndrome and are found in multiple cancer types, including leukaemia,
lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and
regulates cell survival and proliferation primarily through activation of the
RAS–ERK signalling pathway. It is also a key mediator of the programmed cell
death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint
pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a
potential target of cancer therapy. Here we report the discovery of a highly
potent (IC50 = 0.071 μM), selective and orally bioavailable
small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited
conformation. SHP099 concurrently binds to the interface of the N-terminal SH2,
C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2
activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling
to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer
cells in vitro and is efficacious in mouse tumour xenograft models. Together,
these data demonstrate that pharmacological inhibition of SHP2 is a valid
therapeutic approach for the treatment of cancers.
|
|
|
|
|
|
|
