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Blocking EGFR Activation with Anti‐EGF Nanobodies via Two Distinct Molecular Recognition Mechanisms
Author(s) -
Guardiola Salvador,
Varese Monica,
SánchezNavarro Macarena,
Vincke Cécile,
Teixidó Meritxell,
García Jesús,
Muyldermans Serge,
Giralt Ernest
Publication year - 2018
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201807736
Subject(s) - phosphorylation , mechanism (biology) , epidermal growth factor receptor , cancer research , blocking (statistics) , chemistry , epidermal growth factor , microbiology and biotechnology , mechanism of action , computational biology , receptor , biology , biochemistry , computer science , in vitro , computer network , philosophy , epistemology
One of the hallmarks of cancer is the overproduction of growth factors such as EGF. Despite the clinical success achieved by EGFR‐targeted therapies, their long‐term efficacy is compromised by the onset of drug‐resistant mutations. To address this issue, a family of camelid‐derived single‐domain antibodies (Nbs) were generated, obtaining the first direct EGF inhibitors that prevent EGFR phosphorylation and pathway activation through this new mechanism of action. The two best Nbs were subjected to a detailed investigation of their interaction mechanism that revealed important differences in their binding kinetics and equilibrium thermodynamics. These distinct behaviors at the biophysical level translate into an equally efficient inhibition of the cellular EGFR phosphorylation, thus proving the efficacy of these Nbs to turn off the initiation of this key oncogenic pathway in cancer cells.