Using Target Engagement Biomarkers to Predict Clinical Efficacy of MetAP2 Inhibitors
| العنوان: | Using Target Engagement Biomarkers to Predict Clinical Efficacy of MetAP2 Inhibitors |
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| المؤلفون: | Paul Rolzin, Jennifer Matuszkiewicz, James Bilakovics, Alok Pachori, Christopher J. Zopf, Pamela Farrell, Huey-Jing Huang, Artur Plonowski, Urmi Banerjee, Andrea Fanjul, Christopher McBride, Christopher J. Larson, Corine Holub, Zacharia Cheruvallath, Jacques Ermolieff, Darian Bartkowski, Crystal Mazur, Deepika Balakrishna |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 371:299-308 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Drug, media_common.quotation_subject, Angiogenesis Inhibitors, Pharmacology, Chlorobenzenes, Mice, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Cyclohexanes, Predictive Value of Tests, Weight loss, Human Umbilical Vein Endothelial Cells, Animals, Humans, Methionyl Aminopeptidases, Medicine, media_common, Dose-Response Relationship, Drug, business.industry, Biological activity, Mice, Inbred C57BL, Clinical trial, Treatment Outcome, 030104 developmental biology, Drug development, Cinnamates, Pharmacodynamics, Epoxy Compounds, Molecular Medicine, Biomarker (medicine), medicine.symptom, business, Sesquiterpenes, Biomarkers, 030217 neurology & neurosurgery, HeLa Cells |
| الوصف: | Target-engagement pharmacodynamic (PD) biomarkers are valuable tools in the prioritization of drug candidates, especially for novel, first-in-class mechanisms whose robustness to alter disease outcome is unknown. Methionine aminopeptidase 2 (MetAP2) is a cytosolic metalloenzyme that cleaves the N-terminal methionine from nascent proteins. Inhibition of MetAP2 leads to weight loss in obese rodents, dogs and humans. However, there is a need to develop efficacious compounds that specifically inhibit MetAP2 with an improved safety profile. The objective of this study was to identify a PD biomarker for selecting potent, efficacious compounds and for predicting clinical efficacy that would result from inhibition of MetAP2. Here we report the use of NMet14-3-3γ for this purpose. Treatment of primary human cells with MetAP2 inhibitors resulted in an approx. 10-fold increase in NMet14-3-3γ levels. Furthermore, treatment of diet-induced obese mice with these compounds reduced body weight (approx. 20%) and increased NMet14-3-3γ (approx. 15-fold) in adipose tissues. The effects on target engagement and body weight increased over time and were dependent on dose and administration frequency of compound. The relationship between compound concentration in plasma, NMet14-3-3γ in tissue, and reduction of body weight in obese mice was used to generate a pharmacokinetic-pharmacodynamic-efficacy model for predicting efficacy of MetAP2 inhibitors in mice. We also developed a model for predicting weight loss in humans using a target engagement PD assay that measures inhibitor-bound MetAP2 in blood. In summary, MetAP2 target engagement biomarkers can be used to select efficacious compounds and predict weight loss in humans. SIGNIFICANCE STATEMENT: The application of target engagement pharmacodynamic biomarkers during drug development provides a means to determine the dose required to fully engage the intended target and an approach to connect the drug target to physiological effects. This work exemplifies the process of using target engagement biomarkers during preclinical research to select new drug candidates and predict clinical efficacy. We determine concentration of MetAP2 antiobesity compounds needed to produce pharmacological activity in primary human cells and in target tissues from an appropriate animal model and establish key relationships between pharmacokinetics, pharmacodynamics, and efficacy, including the duration of effects after drug administration. The biomarkers described here can aid decision-making in early clinical trials of MetAP2 inhibitors for the treatment of obesity. |
| تدمد: | 1521-0103 0022-3565 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::190c881ee391f64b555b89dd5b10a54a https://doi.org/10.1124/jpet.119.259028 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....190c881ee391f64b555b89dd5b10a54a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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