6V9J

Expanding the Chemical Landscape of SOS1 Activators Using Fragment Based Methods

6V9J の概要

• エントリーDOI: 10.2210/pdb6v9j/pdb
• 分子名称: GTPase HRas, Son of sevenless homolog 1, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (10 entities in total)
• 機能のキーワード: ras, sos, inhibitor, oncoprotein, protein-protein complex, mapk, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 95752.79

構造登録者

Phan, J.,Fesik, S.W. (登録日: 2019-12-13, 公開日: 2020-08-26, 最終更新日: 2024-11-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.76 Å)