Abstract 2200: Dual pocket binding novel tankyrase inhibitor, K-476, enhances the efficacy of immune checkpoint inhibitor by attracting CD8+ T cells into tumor

Abstract

Introduction: Wnt/β-catenin pathway regulates many biological processes such as cell proliferation, stem cell renewal and tissue differentiation. Activation of Wnt/β-catenin pathway has been reported in many cancers. Tankyrase, one of the positive regulators of Wnt/β-catenin pathway, induces degradation of Axin, a negative regulator of Wnt/β-catenin pathway. Therefore, tankyrase inhibition stabilizes Axin protein and inhibits Wnt/β-catenin pathway, leading to exert antitumor effect. Recently, the role of Wnt/β-catenin pathway in immunotherapy has also gained attention; aberrant activation of Wnt/β-catenin pathway causes inactivation of dendritic cells and suppresses chemokine production resulting in paucity of CD8 T+ cells in tumor tissue. Although immune checkpoint inhibitors (ICIs), such as anti-CTLA-4 and anti-PD-1/PD-L1 antibodies have been successfully approved in some cancer therapies, some patients are still resistant to ICIs. One of the main causes is considered to be immune-desert tumor microenvironment, characterized by the absence of infiltrating lymphocytes including CD8+ T cells, cytotoxic effector cells for immunotherapy. Thus, Wnt/β-catenin pathway inhibition may overcome the resistance of anti-PD-1/PD-L1 therapy by attracting CD8+ T cells into tumor. K-476 is a highly potent and selective tankyrase inhibitor synthesized in house. In this study, we investigated whether K-476 enhanced the antitumor effect of anti-PD-L1 antibody. Furthermore, since tankyrase inhibitors are reported to have a potential gastrointestinal toxicity, we also evaluated the toxicity in mice administrated with K-476. Methods and results: Antitumor effect of K-476 combined with anti-PD-L1 antibody was evaluated in B16-derived melanoma bearing mice. Although K-476 monotherapy did not show antitumor effect, a combination with anti-PD-L1 antibody demonstrated a significant antitumor effect at doses from 50 to 200 mg/kg compared to anti-PD-L1 antibody alone, and the magnitude of the effect was comparable among the doses tested. Axin stabilization was observed in tumors after administration of K-476, suggesting that the effect was exerted through inhibition of Wnt/β-catenin pathway. The expression of chemokines, Ccl3 and Ccl4 which attract CD8+ T cells, was also upregulated. In addition, significant increase of CD8+ T cells was observed in the tumor. Gastrointestinal toxicity was not observed up to 200 mg/kg of K-476 in C57BL/6J mice. These results suggested that K-476 enhanced antitumor effect of anti-PD-L1 antibody through upregulation of Ccl3 and Ccl4 production and induction of CD8+ T cells without obvious toxicity. Conclusion: K-476 could be an attractive therapeutic agent that enhances the efficacy of anti-PD-L1 antibody. Citation Format: Haruka Kinosada, Kana Kunieda, Ryoko Okada, Minami Suzuki-Imaizumi, Motoya Mie, Toshihiko Ishii, Ryuichiro Nakai. Dual pocket binding novel tankyrase inhibitor, K-476, enhances the efficacy of immune checkpoint inhibitor by attracting CD8+ T cells into tumor [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2200.

Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II

“…The latter binding mode results in a lower selectivity across the PARP family. Other compounds target both pockets in the catalytic domain. ,− Inhibitors based on the 1,2,4-triazole scaffold such as JW74, G007-LK, OD336, and OM-1700 ( 1 ) target the adenosine binding pocket of the TNKS1/2 catalytic domain with high selectivity and are therefore able to display selectivity over other members of the PARP family.…”

SLC39A1 Overexpression is Associated with Immune Infiltration in Hepatocellular Carcinoma and Promotes Its Malignant Progression

“…In addition, aberrant Wnt signaling pathway in the tumor microenvironment also impairs the cytotoxic T cell infiltration and anti-tumor function, inducing therapeutic resistance to immune checkpoint inhibitors. 33,[52][53][54] Therefore, blocking the Wnt signaling pathway through targeting SLC39A1 may be a promising therapeutic strategy to improve the current HCC immunotherapeutic approaches. Further studies should be performed to elucidate the underlying mechanism of SLC39A1 overexpression in immune cell infiltration in HCC.…”

Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer

“…Very recently, a compound denoted K-476 (49, Figure 11) was reported to bind to both nicotinamide-and adenosinebinding subsites. 175 The chemical structure of K-476 is distinct from any of the aforementioned dual binders, but interactions observed in the crystal structure of this molecule in complex with tankyrase 2 are typical of dual binders (Figure 12C). The nitrile group of K-476 acts as a nicotinamide mimetic and forms a bifurcated hydrogen bond with the backbone amide of G1032 and the hydroxy side chain of S1068; the urea-carbonyl develops a second hydrogen bond with the main chain of Y1060.…”

“…Intriguingly, N-phenylation of K-756 gave rise to K-476 (49, Section 2.4), which turns out to be a dual binder. 175 2.3.2. 1,2,4-TriazolesFrom JW74 through G007-LK, OD336, and OM-1700 to OM-153.…”