7CE4

Tankyrase2 catalytic domain in complex with K-476

Summary for 7CE4

• Entry DOI: 10.2210/pdb7ce4/pdb
• Descriptor: Poly [ADP-ribose] polymerase tankyrase-2, ZINC ION, SULFATE ION, ... (7 entities in total)
• Functional Keywords: tankyrase, parp, adp-ribosylation, transferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 28322.12

Authors

Takahashi, Y.,Suzuki, M.,Saito, J. (deposition date: 2020-06-22, release date: 2021-05-12, Last modification date: 2023-11-29)

Primary citation

Kinosada, H.,Okada-Iwasaki, R.,Kunieda, K.,Suzuki-Imaizumi, M.,Takahashi, Y.,Miyagi, H.,Suzuki, M.,Motosawa, K.,Watanabe, M.,Mie, M.,Ishii, T.,Ishida, H.,Saito, J.I.,Nakai, R.
The dual pocket binding novel tankyrase inhibitor K-476 enhances the efficacy of immune checkpoint inhibitor by attracting CD8 + T cells to tumors.
Am J Cancer Res, 11:264-276, 2021

PubMed 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 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., and ), 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.

PubMed: 33520373

Experimental method

X-RAY DIFFRACTION (1.5 Å)