7AVS

Crystal structure of SOS1 in complex with compound 6

Summary for 7AVS

• Entry DOI: 10.2210/pdb7avs/pdb
• Related: 7AVI 7AVL
• Descriptor: Son of sevenless homolog 1, IMIDAZOLE, 6,7-dimethoxy-2-methyl-~{N}-[(1~{R})-1-[3-(trifluoromethyl)phenyl]ethyl]quinazolin-4-amine, ... (4 entities in total)
• Functional Keywords: rasgef, protein binding
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 115265.68

Authors

Bader, G.,Kessler, D.,Wolkerstorfer, B. (deposition date: 2020-11-06, release date: 2021-03-24, Last modification date: 2024-01-31)

Primary citation

Ramharter, J.,Kessler, D.,Ettmayer, P.,Hofmann, M.H.,Gerstberger, T.,Gmachl, M.,Wunberg, T.,Kofink, C.,Sanderson, M.,Arnhof, H.,Bader, G.,Rumpel, K.,Zophel, A.,Schnitzer, R.,Bottcher, J.,O'Connell, J.C.,Mendes, R.L.,Richard, D.,Pototschnig, N.,Weiner, I.,Hela, W.,Hauer, K.,Haering, D.,Lamarre, L.,Wolkerstorfer, B.,Salamon, C.,Werni, P.,Munico-Martinez, S.,Meyer, R.,Kennedy, M.D.,Kraut, N.,McConnell, D.B.
One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS.
J.Med.Chem., 64:6569-6580, 2021

PubMed Abstract: 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 Y884 and A73 is sufficient to convert SOS1 activators into SOS1 inhibitors. We also disclose the discovery of . Combination with the upstream EGFR inhibitor afatinib shows efficacy against KRAS mutant colorectal tumor cells, demonstrating the utility of 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.

PubMed: 33719426
DOI: 10.1021/acs.jmedchem.0c01949

Experimental method

X-RAY DIFFRACTION (2.28 Å)