6BVI

Ras:SOS:Ras in complex with a small molecule activator

6BVI の概要

• エントリーDOI: 10.2210/pdb6bvi/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: 95892.42

構造登録者

Phan, J.,Abbott, J.,Fesik, S.W. (登録日: 2017-12-13, 公開日: 2018-10-24, 最終更新日: 2024-11-06)

主引用文献

Abbott, J.R.,Hodges, T.R.,Daniels, R.N.,Patel, P.A.,Kennedy, J.P.,Howes, J.E.,Akan, D.T.,Burns, M.C.,Sai, J.,Sobolik, T.,Beesetty, Y.,Lee, T.,Rossanese, O.W.,Phan, J.,Waterson, A.G.,Fesik, S.W.
Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling.
J. Med. Chem., 61:6002-6017, 2018

PubMed Abstract: Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report on structure-activity relationships (SAR) in an indole series of compounds. Using structure-based design, we systematically explored substitution patterns on the indole nucleus, the pendant amino acid moiety, and the linker unit that connects these two fragments. Best-in-class compounds activate the nucleotide exchange process at submicromolar concentrations in vitro, increase levels of active RAS-GTP in HeLa cells, and elicit signaling changes in the mitogen-activated protein kinase-extracellular regulated kinase (MAPK-ERK) pathway, resulting in a decrease in pERK1/2 protein levels at higher compound concentrations.

PubMed: 29856609
DOI: 10.1021/acs.jmedchem.8b00360

実験手法

X-RAY DIFFRACTION (1.746 Å)