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PDBsum entry 6vqn
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References listed in PDB file
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Key reference
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Title
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Checkpoint inhibition through small molecule-Induced internalization of programmed death-Ligand 1.
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Authors
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J.J.Park,
E.P.Thi,
V.H.Carpio,
Y.Bi,
A.G.Cole,
B.D.Dorsey,
K.Fan,
T.Harasym,
C.L.Iott,
S.Kadhim,
J.H.Kim,
A.C.H.Lee,
D.Nguyen,
B.S.Paratala,
R.Qiu,
A.White,
D.Lakshminarasimhan,
C.Leo,
R.K.Suto,
R.Rijnbrand,
S.Tang,
M.J.Sofia,
C.B.Moore.
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Ref.
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Nat Commun, 2021,
12,
1222.
[DOI no: ]
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PubMed id
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Abstract
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Programmed death-ligand 1 is a glycoprotein expressed on antigen presenting
cells, hepatocytes, and tumors which upon interaction with programmed death-1,
results in inhibition of antigen-specific T cell responses. Here, we report a
mechanism of inhibiting programmed death-ligand 1 through small molecule-induced
dimerization and internalization. This represents a mechanism of checkpoint
inhibition, which differentiates from anti-programmed death-ligand 1 antibodies
which function through molecular disruption of the programmed death 1
interaction. Testing of programmed death ligand 1 small molecule inhibition in a
humanized mouse model of colorectal cancer results in a significant reduction in
tumor size and promotes T cell proliferation. In addition, antigen-specific T
and B cell responses from patients with chronic hepatitis B infection are
significantly elevated upon programmed death ligand 1 small molecule inhibitor
treatment. Taken together, these data identify a mechanism of small
molecule-induced programmed death ligand 1 internalization with potential
therapeutic implications in oncology and chronic viral infections.
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