New insight on the structural features of the cytotoxic auristatins MMAE and MMAF revealed by combined NMR spectroscopy and quantum chemical modelling.

摘要: Antibody-drug conjugates (ADCs) are emerging as a promising class of selective drug delivery systems in the battle against cancer and other diseases. The auristatins monomethyl auristatin E (MMAE) F (MMAF) appear cytotoxic almost half state-of-the-art ADCs on market or late stage clinical trials. Here, we present first complete NMR spectroscopic characterisation these challenging molecules, investigate their structural properties by combined quantum chemical modelling approach. We find that solution, molecules locked an inactive conformation, severely decreasing efficiency, potentially increasing risk side-effects. Furthermore, identify sites susceptible to future modification, order improve performance drugs.