Biomimetic N ‐cyano sulfoximine–thiazole ligation for antibody–drug conjugate assembly

We report the first application of N ‐cyano sulfoximine‐mediated thiazole ligation to antibody–drug conjugate (ADC) assembly. A bifunctional N ‐cyano sulfoximine–maleimide linker bearing a pyrimidine core was synthesized and installed on trastuzumab via thiol–maleimide chemistry, as confirmed by ESI‐QTOF analysis of all eight interchain cysteine sites. Subsequent ligation with an N ‐terminal cysteine‐functionalized rhodamine (Cys–rhodamine) model payload under mild aqueous conditions (PBS, pH 7.4) afforded model ADCs with tunable drug‐to‐antibody ratios (DAR). Stepwise payload addition (25 equiv., 2 h intervals) achieved DAR 8 within 10–12 h, corresponding to full occupancy of all conjugation sites. These findings establish biomimetic thiazole ligation as a viable platform for chemo‐selective ADC construction.