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. 2012 Jun 18;51(25):6140-3.
doi: 10.1002/anie.201201358. Epub 2012 May 8.

Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation

Qi Sun  1 , Jason P Burke, Jason Phan, Michael C Burns, Edward T Olejniczak, Alex G Waterson, Taekyu Lee, Olivia W Rossanese, Stephen W Fesik
Affiliations

Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation

Qi Sun et al. Angew Chem Int Ed Engl. .
No abstract available

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Figures

Figure 1
Figure 1
Multiple chemotypes were identified in the fragment-based screen, including indoles (1), phenols (2), and sulfonamides (3). Analogs of these compounds (4, 5, 6) were synthesized to increase their water solubility and binding affinity.
Figure 2
Figure 2
Ribbon and molecular surface representations of the X-ray co-crystal structures of GDP-K-Ras complexed to: a) 4 (PDB code 4EPV), b) 5 (PDB code 4EPW), c) 2 (PDB code 4EPT) and d) 6 (PDB code 4EPX).
Figure 3
Figure 3
Electrostatic surface representations of GDP-K-Ras a) in the absence of a ligand (PDB code 4EPR) and b) in the “open” form showing the primary hydrophobic binding pocket and the adjacent electronegative cleft. c) Schematic representation of the transition of GDP-K-Ras from the “closed” form (green) to the “open” form (cyan).
Figure 4
Figure 4
a) Ribbon and molecular surface representations of GDP-bound K-Ras complexed to 13 (PDB code 4EPY). b) K-Ras/13 X-ray structure overlaid with a previously reported[9] Ras-Sos complex crystal structure (PDB code 1BKD).
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