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Comparative analysis of two NNMT bisubstrate inhibitors through chemoproteomic studies: uncovering the role of unconventional SAM analogue moiety for improved selectivity

Zarzycki MZ, Domitrz I

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Side-by-Side Comparison Parameter Receptors Cagrilintide AMY1R/2R/3R + CTR Semaglutide GLP-1R Tirzepatide GLP-1R + GIPR Retatrutide GLP-1R + GIPR + Glucagon-R Parameter Half-life Cagrilintide ~7-8 days Semaglutide ~7 days Tirzepatide ~5 days Retatrutide ~6 days Parameter Dosing frequency Cagrilintide Once weekly Semaglutide Once weekly Tirzepatide Once weekly Retatrutide Once weekly Parameter Max studied dose Cagrilintide 4.5 mg/week (mono) Semaglutide 2.4 mg/week Tirzepatide 15 mg/week Retatrutide 12 mg/week Parameter Peak monotherapy weight loss Cagrilintide 11.8% at 68 wk Semaglutide 14.9-17% at 68 wk Tirzepatide 22.5% at 72 wk Retatrutide ~24% at 48 wk Parameter FDA status (June 2026) Cagrilintide Investigational Semaglutide Approved (2021) Tirzepatide Approved (2023) Retatrutide Investigational Parameter HbA1c reduction (T2D) Cagrilintide ~0.9 pp mono