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PDBsum entry 7ce4
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Transferase/transferase inhibitor
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PDB id
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7ce4
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References listed in PDB file
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Key reference
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Title
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The dual pocket binding novel tankyrase inhibitor k-476 enhances the efficacy of immune checkpoint inhibitor by attracting cd8+ t cells to tumors.
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Authors
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H.Kinosada,
R.Okada-Iwasaki,
K.Kunieda,
M.Suzuki-Imaizumi,
Y.Takahashi,
H.Miyagi,
M.Suzuki,
K.Motosawa,
M.Watanabe,
M.Mie,
T.Ishii,
H.Ishida,
J.I.Saito,
R.Nakai.
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Ref.
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Am J Cancer Res, 2021,
11,
264-276.
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PubMed id
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Abstract
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The Wnt/β-catenin pathway, which is associated with disease progression, is
activated in many cancers. Tankyrase (TNKS) has received attention as a target
molecule for Wnt/β-catenin pathway inhibition. We identified K-476, a novel
TNKS inhibitor, a dual pocket binder that binds to both the nicotinamide and
ADP-ribose pockets. In a human colon cancer cell line, K-476 specifically and
potently inhibited TNKS and led to stabilization of the Axin protein, resulting
in Wnt/β-catenin pathway suppression. Aberrant Wnt/β-catenin pathway
activation was recently reported as a possible mechanism of ineffectiveness in
immune checkpoint inhibitor (ICI) treatment. Because the Wnt/β-catenin pathway
activation causes dendritic cell inactivation and suppresses chemokine
production, resulting in a paucity of CD8+ T cells in tumor tissue,
which is an important effector of ICIs. Thus, TNKS inhibitors may enhance the
efficacy of ICIs. To examine whether K-476 enhances the antitumor effect of
anti-PD-L1 antibodies, K-476 was administered orally with an anti-PD-L1 antibody
to melanoma-bearing C57BL/6J mice. Although K-476 was ineffective as a
monotherapy, it significantly enhanced the antitumor effect in combination with
anti-PD-L1 antibody. In mice, intra-tumor infiltration of CD8+ T
cells was increased by combination treatment. K-476 upregulated the chemokine
expression (e.g., Ccl3 and Ccl4), which attracted CD8+
T cells. This was considered to contribute to the increased CD8+ T
cells in the tumor microenvironment. Furthermore, while the potential
gastrointestinal toxicity of TNKS inhibitors has been reported, it was not
observed at effective doses. Thus, K-476 could be an attractive therapeutic
option to enhance the efficacy of ICIs.
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