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

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...

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Bibliographic Details
Published in:Scientific reports 2017-11, Vol.7 (1), p.15920-10, Article 15920
Main Authors: Johansson, Mikael P., Maaheimo, Hannu, Ekholm, Filip S.
Format: Article
Language:English
Subjects:
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631/67
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639/638/92/606
Cancer
Clinical trials
Conformation
Cytotoxicity
Drug delivery
Humanities and Social Sciences
Magnetic resonance spectroscopy
multidisciplinary
NMR
Nuclear magnetic resonance
Science
Science (multidisciplinary)
Side effects
Spectroscopy
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-15674-1