The dual pocket binding novel tankyrase inhibitor K-476 enhances the efficacy of immune checkpoint inhibitor by attracting CD8⁺ T cells to tumors.

ABSTRACT: 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 o

SUBMITTER: Kinosada H 

PROVIDER: S-EPMC7840722 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature