Adrian D Hobson, Jianwen Xu, Dennie S Welch, Christopher C Marvin, Michael J McPherson, Bradley Gates, Xiaoli Liao, Markus Hollmann, Michael J Gattner, Kristina Dzeyk, Hetal Sarvaiya, Vikram M Shenoy, Margaret M Fettis, Agnieszka K Bischoff, Lu Wang, Ling C Santora, Lu Wang, Julia Fitzgibbons, Paulin Salomon, Axel Hernandez, Ying Jia, Christian A Goess, Suzanne L Mathieu, Shaughn H Bryant, Mary E Larsen, Baoliang Cui, Yu Tian
Stable attachment of drug-linkers to the antibody is a critical requirement, and for maleimide conjugation to cysteine, it is achieved by ring hydrolysis of the succinimide ring. During ADC profiling in our in-house property screening funnel, we discovered that the succinimide ring open form is in equilibrium with the ring closed succinimide. Bromoacetamide (BrAc) was identified as the optimal replacement, as it affords stable attachment of the drug-linker to the antibody while completely removing the undesired ring open-closed equilibrium...
September 1, 2023: Journal of Medicinal Chemistry