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

Abstract

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 peroral (PO) administration of 0.33-10 mg/kg twice daily (BID). In addition, OM-153 potentiates anti-PD-1 immune checkpoint inhibition and anti-tumor 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 PO-BID administration of 100 mg/kg. In contrast, mice treated PO-BID with 10 mg/kg show an intact intestinal architecture and no atypical histopathological changes in other organs. In addition, clinical biochemistry and haematological analyses do not identify changes indicating substantial toxicity. The results demonstrate OM-153-mediated anti-tumor 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.

An Evolutionary Perspective on the Origin, Conservation and Binding Partner Acquisition of Tankyrases

“…To further demonstrate the high similarity between the ART domains of Aq TNKS and TNKS1, we tested the thermal stabilization with established potent and selective TNKS inhibitors that were recently benchmarked [ 50 ]. This included adenosine-site binders IWR-1, G007-LK, OM-153 and compound 40 [ 74 , 75 , 76 , 77 ], nicotinamide-site binders XAV939, E7449, AZ6102 [ 10 , 78 , 79 ] and the dual-site binder NVP-TNKS656 [ 80 ].…”

“…Samples of ART constructs (5 μM) from TNKS1 or Aq TNKS were prepared in absence or presence of TNKS inhibitors (25 μM) IWR-1, G007-LK, OM-153, compound 40, XAV939, E7449 or NVP-TNKS656 [ 50 ] and 5× SYPRO orange dye (ThermoFisher Scientific). Each condition was prepared in 4 replicates with a final volume of 20 μL.…”

An evolutionary perspective on the origin, conservation and binding partner acquisition of tankyrases

“…To further demonstrate the high similarity between the ART domains of Aq TNKS and TNKS1, we tested the thermal stabilization with established potent and selective TNKS inhibitors that were recently benchmarked (Brinch et al, 2022). This included adenosine site binders IWR-1, G007-LK, OM-153 and compound 40 (Bregman et al, 2013; Chen et al, 2009; Leenders et al, 2021; Voronkov et al, 2013), nicotinamide-site binders XAV939, E7449, AZ6102 (Huang et al, 2009; Johannes et al, 2015; McGonigle et al, 2015) and the dual-site binder NVP-TNKS656 (Shultz et al, 2013).…”

“…Samples of ART constructs (5 μM) from TNKS1 or Aq TNKS were prepared in absence or presence of TNKS inhibitors (25 μM) IWR-1, G007-LK, OM-153, compound 40, XAV939, E7449 or NVP-TNKS656 (Brinch et al, 2022) and 5x SYPRO orange dye (ThermoFisher Scientific). Each condition was prepared in 4 replicates with a final volume of 20 μL.…”

A Mouse Model for the Rapid and Binomial Assessment of Putative WNT/β-Catenin Signalling Inhibitors

“…The canonical WNT/β-catenin signalling pathway provides the core of an evolutionary conserved, fundamental pathway that controls growth and governs numerous developmental processes, while its aberrant regulation contributes to many diseases including cancer [1][2][3]. Despite more than two decades of development to identify WNT/β-catenin signalling inhibitors [4][5][6], including G007-LK-series tankyrase inhibitors [7][8][9][10], no drug has so far reached clinical use. This is in part due to the lack of suitable whole animal models that allow for the rapid and unambiguous monitoring of on-target activity, while simultaneously predicting side effects that may arise from the broad and iterative use of the WNT/β-catenin signalling pathway for homeostatic tissue renewal throughout adult life [11].…”