The Tankyrase Inhibitor OM-153 Demonstrates Antitumor Efficacy and a Therapeutic Window in Mouse Models.

The catalytic enzymes tankyrase 1 and 2 (TNKS1/2) alter protein turnover by poly-ADP-ribosylating target proteins, which earmark them for degradation by the ubiquitin-proteasomal system. Prominent targets of the catalytic activity of TNKS1/2 include AXIN proteins, resulting in TNKS1/2 being attractive biotargets for addressing of oncogenic WNT/β-catenin signaling. Although several potent small molecules have been developed to inhibit TNKS1/2, there are currently no TNKS1/2 inhibitors available in clinical practice. The development of tankyrase inhibitors has mainly been disadvantaged by concerns over biotarget-dependent intestinal toxicity and a deficient therapeutic window. Here we show that the novel, potent, and selective 1,2,4-triazole-based TNKS1/2 inhibitor OM-153 reduces WNT/β-catenin signaling and tumor progression in COLO 320DM colon carcinoma xenografts upon oral administration of 0.33-10 mg/kg twice daily. In addition, OM-153 potentiates anti-programmed cell death protein 1 (anti-PD-1) immune checkpoint inhibition and antitumor effect in a B16-F10 mouse melanoma model. A 28-day repeated dose mouse toxicity study documents body weight loss, intestinal damage, and tubular damage in the kidney after oral-twice daily administration of 100 mg/kg. In contrast, mice treated oral-twice daily with 10 mg/kg show an intact intestinal architecture and no atypical histopathologic changes in other organs. In addition, clinical biochemistry and hematologic analyses do not identify changes indicating substantial toxicity. The results demonstrate OM-153-mediated antitumor effects and a therapeutic window in a colon carcinoma mouse model ranging from 0.33 to at least 10 mg/kg, and provide a framework for using OM-153 for further preclinical evaluations. This study uncovers the effectiveness and therapeutic window for a novel tankyrase inhibitor in mouse tumor models.

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© 2022 The Authors; Published by the American Association for Cancer Research.

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G. Grødeland reports personal fees from AstraZeneca, Sanofi, Bayer, Thermo Fisher, and personal fees from Norwegian System for compensation to patients outside the submitted work. S.T. Sowa reports grants from Jane and Aatos Erkko Foundation during the conduct of the study. L. Lehtiö reports a patent to WO2019/243822 issued and a patent to WO2022/008896 issued. R.G. Leenders reports a patent to WO2019/243822 issued and a patent to WO2022/008896 issued (the drug development project is 100% owned by the Oslo University Hospital and administered by the TTO Inven2; Symeres Inc. has a scientific and BD collaboration agreement with Inven2). A. Wegert reports a patent to WO2019/243822 issued and a patent to WO2022/008896 issued (the drug development project is 100% owned by the Oslo University hospital and administered by the TTO Inven2; Symeres B.V. has a scientific and BD collaboration agreement with Inven2). S. Krauss reports a patent to WO2019/243822 issued and a patent to WO2022/008896 issued (the drug development program is 100% owned by the Oslo University Hospital and administered by the TTO Inven2; Symeres Inc. has a scientific and BD collaboration agreement with Inven2 on the drug development program). J. Waaler reports a patent to WO2019/243822 issued and a patent to WO2022/008896 issued (the drug development project is 100% owned by the Oslo University Hospital and administered by the TTO Inven2). Our project collaborator Symeres Inc. has a scientific and BD collaboration agreement with Inven2. No disclosures were reported by the other authors.