PDBsum entry 7ce4

Transferase/transferase inhibitor

PDB id: 7ce4

Contents

Protein chains

162 a.a.

45 a.a.

Ligands

SO4 ×2

KK6

PG4

Metals

_ZN

Waters ×275

PDB id:

7ce4

Name:

Transferase/transferase inhibitor

Title:

Tankyrase2 catalytic domain in complex with k-476

Structure:

Poly [adp-ribose] polymerase tankyrase-2. Chain: a. Fragment: catalytic domain. Synonym: adp-ribosyltransferase diphtheria toxin-like 6,artd6,poly [adp-ribose] polymerase 5b,protein poly-adp-ribosyltransferase tankyrase-2,tnks-2,trf1-interacting ankyrin-related adp-ribose polymerase 2,tankyrase ii,tankyrase-2,tank2,tankyrase-like protein, tankyrase-related protein. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tnks2, parp5b, tank2, tnkl. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Resolution:

1.50Å R-factor: 0.174 R-free: 0.203

Authors:

Y.Takahashi,M.Suzuki,J.Saito

Key ref:

H.Kinosada et al. (2021). 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. PubMed id: 33520373

Date:

22-Jun-20 Release date: 12-May-21

Protein chain

Q9H2K2  (TNKS2_HUMAN) -  Poly [ADP-ribose] polymerase tankyrase-2 from Homo sapiens

Seq: 1166 a.a.

Struc: 162 a.a.

Protein chain

Q9H2K2  (TNKS2_HUMAN) -  Poly [ADP-ribose] polymerase tankyrase-2 from Homo sapiens

Seq: 1166 a.a.

Struc: 45 a.a.

Enzyme reactions

• Enzyme class 2: Chains A, B: E.C.2.4.2.- - ?????
• Enzyme class 3: Chains A, B: E.C.2.4.2.30 - NAD(+) ADP-ribosyltransferase.

Pathway:

• Reaction: NAD⁺ + (ADP-D-ribosyl)n-acceptor = nicotinamide + (ADP-D- ribosyl)n+1-acceptor + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

Am J Cancer Res 11:264-276 (2021)

PubMed id: 33520373

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

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.

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., 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.