l-citrulline: A preclinical safety biomarker for the small intestine in rats and dogs in repeat dose toxicity studies

Jäckel, Sven; Pipp, Frederic; Emde, Barbara; Weigt, Stefan; Vigna, Enrico; Hanschke, Bettina; Kasper, Lena; Siddharta, Anindya; Hellmann, Jürgen; Czasch, Stephanie; Schmitt, Michael

doi:10.1016/j.vascn.2021.107068

Cited by 4 publications

(2 citation statements)

References 21 publications

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“…The dose of 20 mg/kg bi-daily was tolerated based on clinical signs and body weight (Supporting Information, Figure S6b,c). In addition, plasma levels of Lcitrulline, a well-characterized preclinical safety biomarker for gastrointestinal toxicity, 29,30 were not affected in mice treated for 17 days with 20 mg/kg bi-daily of M2912 (30g) (Supporting Information, Figure S7). However, at higher doses of 50 mg/kg bi-daily, adverse histopathological findings were observed in the gastrointestinal tract, which was previously described as the key target organ for tankyrase inhibitors.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Optimization of a Screening Hit toward M2912, an Oral Tankyrase Inhibitor with Antitumor Activity in Colorectal Cancer Models

et al. 2021

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Constitutive activation of the canonical Wnt signaling pathway, in most cases driven by inactivation of the tumor suppressor APC, is a hallmark of colorectal cancer. Tankyrases are druggable key regulators in these malignancies and are considered as attractive targets for therapeutic interventions, although no inhibitor has been progressed to clinical development yet. We continued our efforts to develop tankyrase inhibitors targeting the nicotinamide pocket with suitable drug-like properties for investigating effects of Wnt pathway inhibition on tumor growth. Herein, the identification of a screening hit series and its optimization through scaffold hopping and SAR exploration is described. The systematic assessment delivered M2912, a compound with an optimal balance between excellent TNKS potency, exquisite PARP selectivity, and a predicted human PK compatible with once daily oral dosing. Modulation of cellular Wnt pathway activity and significant tumor growth inhibition was demonstrated with this compound in colorectal xenograft models in vivo.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Optimization of a Screening Hit toward M2912, an Oral Tankyrase Inhibitor with Antitumor Activity in Colorectal Cancer Models

et al. 2021

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“…Clinically, L-citrulline is a recognized biomarker of intestinal tissue integrity ( Bujold et al, 2016 ). In this issue, Jäckel et al (2021) examined the potential role of L-citrulline in toxicology studies conducted in common laboratory animal species for use in the GI safety evaluation of oncology drug candidates. The authors validated a simple bioanalytical method for L-citrulline quantification in plasma.…”

Section: Biomarkers In Safety Pharmacology Studiesmentioning

confidence: 99%

Safety pharmacology during the COVID pandemic

Koshman

Korte²,

Authier³

et al. 2021

Journal of Pharmacological and Toxicological Methods

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This editorial summarizes the content of the current themed issue of J Pharmacol Toxicol Methods derived from the 2020 Annual Safety Pharmacology Society (SPS) meeting that was held virtually September 14–17, 2020 due to the ongoing COVID-19 global pandemic. A selection of articles arising from the virtual meeting is summarized. Like previous years they continue to reflect current areas of innovation in SP including new methodologies to predict human safety, best practices for IKr current measurement, and best practice considerations for the conduct of in vivo nonclinical QT studies. The meeting included scientific content from 94 abstracts (reproduced in the current volume of J Pharmacol Toxicol Methods ). This continued innovation reflects a rubric in SP that identifies problems, seeks solutions and, importantly, validates the solutions.

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Morphological Assessment and Biomarkers of Low-Grade, Chronic Intestinal Inflammation in Production Animals

Soares¹,

Belote²,

Santín³

et al. 2022

Animals

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The complex interaction between the intestinal mucosa, the gut microbiota, and the diet balances the host physiological homeostasis and is fundamental for the maximal genetic potential of production animals. However, factors such as chemical and physical characteristics of the diet and/or environmental stressors can continuously affect this balance, potentially inducing a state of chronic low-grade inflammation in the gut, where inflammatory parameters are present and demanding energy, but not in enough intensity to provoke clinical manifestations. It’s vital to expand the understanding of inflammation dynamics and of how they compromise the function activity and microscopic morphology of the intestinal mucosa. These morphometric alterations are associated with the release of structural and functional cellular components into the feces and the blood stream creating measurable biomarkers to track this condition. Moreover, the identification of novel, immunometabolic biomarkers can provide dynamic and predictors of low-grade chronic inflammation, but also provide indicators of successful nutritional or feed additive intervention strategies. The objective of this paper is to review the mechanisms of low-grade inflammation, its effects on animal production and sustainability, and the biomarkers that could provide early diagnosis of this process and support studies of useful interventional strategies.

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l-citrulline: A preclinical safety biomarker for the small intestine in rats and dogs in repeat dose toxicity studies

Cited by 4 publications

References 21 publications

Optimization of a Screening Hit toward M2912, an Oral Tankyrase Inhibitor with Antitumor Activity in Colorectal Cancer Models

Optimization of a Screening Hit toward M2912, an Oral Tankyrase Inhibitor with Antitumor Activity in Colorectal Cancer Models

Safety pharmacology during the COVID pandemic

Morphological Assessment and Biomarkers of Low-Grade, Chronic Intestinal Inflammation in Production Animals

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