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8701774 
Journal Article 
Using target engagement biomarkers to predict clinical efficacy of MeTAP2 inhibitors 
Farrell, PJ; Zopf, CJ; Huang, HJ; Balakrishna, D; Holub, C; Bilakovics, J; Fanjul, A; Matuszkiewicz, J; Plonowski, A; Rolzin, P; Banerjee, U; Ermolieff, J; Cheruvallath, ZS; Mcbride, C; Bartkowski, D; Mazur, C; Pachori, A; Larson, CJ 
2019 
Yes 
Journal of Pharmacology and Experimental Therapeutics
ISSN: 0022-3565
EISSN: 1521-0103 
371 
2 
299-308 
English 
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 NMet14-3-3g for this purpose. Treatment of primary human cells with MetAP2 inhibitors resulted in an approx. 10-fold increase in NMet14-3-3g levels. Furthermore, treatment of diet-induced obese mice with these compounds reduced body weight (approx. 20%) and increased NMet14-3-3g (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, NMet14-3-3g 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. 2019 American Society for Pharmacology and Experimental Therapy. All rights reserved.