Abstract

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

Details

Title
New insight on the structural features of the cytotoxic auristatins MMAE and MMAF revealed by combined NMR spectroscopy and quantum chemical modelling
Author
Johansson, Mikael P 1   VIAFID ORCID Logo  ; Maaheimo, Hannu 2   VIAFID ORCID Logo  ; Ekholm, Filip S 3 

 Department of Chemistry, University of Helsinki, PO Box 55, A. I. Virtasen aukio 1, 00014 Helsinki, Finland 
 VTT Technical Research Centre of Finland Ltd, PO Box 1000, 02044 VTT, Finland 
 Department of Chemistry, University of Helsinki, PO Box 55, A. I. Virtasen aukio 1, 00014 Helsinki, Finland; Glykos Finland Ltd, Viikinkaari 6, Helsinki, Finland 
Pages
1-10
Publication year
2017
Publication date
Nov 2017
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1967046775
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.