One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS
| Autor: | Reiner Meyer, Heribert Arnhof, Daniela Haering, Rachel L Mendes, David J. Richard, Irene Weiner, Norbert Kraut, Wolfgang Hela, Christian Salamon, Klaus Rumpel, Gerd Bader, Michael Gmachl, Andreas Dr. Zöphel, Renate Schnitzer, Peter Ettmayer, Jark Böttcher, Matthew D Kennedy, Juergen Ramharter, Michael P. Sanderson, Darryl B. McConnell, Nikolai Pototschnig, Dirk Kessler, Silvia Munico-Martinez, Tobias Wunberg, Marco H. Hofmann, Katja Hauer, Thomas Gerstberger, Lyne Lamarre, Patrick Werni, Christiane Kofink, Jonathan O’Connell, Bernhard Wolkerstorfer |
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| Rok vydání: | 2021 |
| Předmět: |
Afatinib
Mutagenesis (molecular biology technique) Molecular Dynamics Simulation medicine.disease_cause 01 natural sciences Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Allosteric Regulation Catalytic Domain Drug Discovery medicine Humans Protein Interaction Maps Colorectal tumor 030304 developmental biology EGFR inhibitors 0303 health sciences Binding Sites Chemistry 0104 chemical sciences ErbB Receptors 010404 medicinal & biomolecular chemistry Cancer research SOS1 Mutagenesis Site-Directed Quinazolines Molecular Medicine KRAS Colorectal Neoplasms SOS1 Protein medicine.drug Foot-in-the-door technique |
| Zdroj: | Journal of medicinal chemistry. 64(10) |
| ISSN: | 1520-4804 |
| Popis: | KRAS, the most common oncogenic driver in human cancers, is controlled and signals primarily through protein-protein interactions (PPIs). The interaction between KRAS and SOS1, crucial for the activation of KRAS, is a typical, challenging PPI with a large contact surface area and high affinity. Here, we report that the addition of only one atom placed between Y884SOS1 and A73KRAS is sufficient to convert SOS1 activators into SOS1 inhibitors. We also disclose the discovery of BI-3406. Combination with the upstream EGFR inhibitor afatinib shows in vivo efficacy against KRASG13D mutant colorectal tumor cells, demonstrating the utility of BI-3406 to probe SOS1 biology. These findings challenge the dogma that large molecules are required to disrupt challenging PPIs. Instead, a "foot in the door" approach, whereby single atoms or small functional groups placed between key PPI interactions, can lead to potent inhibitors even for challenging PPIs such as SOS1-KRAS. |
| Databáze: | OpenAIRE |
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