6V9M

Expanding the Chemical Landscape of SOS1 Activators Using Fragment Based Methods

Summary for 6V9M

• Entry DOI: 10.2210/pdb6v9m/pdb
• Descriptor: GTPase HRas, Son of sevenless homolog 1, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (10 entities in total)
• Functional Keywords: ras, sos, inhibitor, oncoprotein, protein-protein complex, mapk, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 95639.28

Authors

Phan, J.,Fesik, S.W. (deposition date: 2019-12-13, release date: 2020-08-26, Last modification date: 2024-11-06)

Primary citation

Sarkar, D.,Olejniczak, E.T.,Phan, J.,Coker, J.A.,Sai, J.,Arnold, A.,Beesetty, Y.,Waterson, A.G.,Fesik, S.W.
Discovery of Sulfonamide-Derived Agonists of SOS1-Mediated Nucleotide Exchange on RAS Using Fragment-Based Methods.
J.Med.Chem., 63:8325-8337, 2020

PubMed Abstract: The nucleotide exchange factor Son of Sevenless (SOS) catalyzes the activation of RAS by converting it from its inactive GDP-bound state to its active GTP-bound state. Recently, we have reported the discovery of small-molecule allosteric activators of SOS1 that can increase the amount of RAS-GTP in cells. The compounds can inhibit ERK phosphorylation at higher concentrations by engaging a feedback mechanism. To further study this process, we sought different chemical matter from an NMR-based fragment screen using selective methyl labeling. To aid this process, several Ile methyl groups located in different binding sites of the protein were assigned and used to categorize the NMR hits into different classes. Hit to lead optimization using an iterative structure-based design paradigm resulted in compounds with improvements in binding affinity. These improved molecules of a different chemical class increase SOS1-mediated nucleotide exchange on RAS and display cellular action consistent with our prior results.

PubMed: 32673492
DOI: 10.1021/acs.jmedchem.0c00511

Experimental method

X-RAY DIFFRACTION (1.648 Å)