Discovery of Five SOS2 Fragment Hits with Binding Modes Determined by SOS2 X-Ray Cocrystallography.

Publication Type:

Journal Article

Authors:

Smith, Christopher R; Chen, Dan; Christensen, James G; Coulombe, René; Féthière, James; Gunn, Robin J; Hollander, Johan; Jones, Benjamin; Ketcham, John M; Khare, Shilpi; Kuehler, Jon; Lawson, J David; Marx, Matthew A; Olson, Peter; Pearson, Kelly E; Ren, Cynthia; Tsagris, Denise; Ulaganathan, Thirumalaiselvi; Van't Veer, Inge; Wang, Xiaolun; Ivetac, Anthony

Source:

J Med Chem, Volume 67, Issue 1, p.774-781 (2024)

Keywords:

Cell Line, Furans, Guanine Nucleotide Exchange Factors, Proto-Oncogene Proteins p21(ras), Quinazolines, SOS1 Protein, X-Rays

Abstract:

<p>SOS1 and SOS2 are guanine nucleotide exchange factors that mediate RTK-stimulated RAS activation. Selective SOS1:KRAS PPI inhibitors are currently under clinical investigation, whereas there are no reports to date of SOS2:KRAS PPI inhibitors. SOS2 activity is implicated in MAPK rebound when divergent SOS1 mutant cell lines are treated with the SOS1 inhibitor BI-3406; therefore, SOS2:KRAS inhibitors are of therapeutic interest. In this report, we detail a fragment-based screening strategy to identify X-ray cocrystal structures of five diverse fragment hits bound to SOS2.</p>

PDB: 
8T5G, 8T5M, 8T5R, 8UC9, 8UF2, 8UH0
Detector: 
EIGER
Beamline: 
24-ID-E