6CUP

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

6CUP の概要

• エントリーDOI: 10.2210/pdb6cup/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: 95764.82

構造登録者

Phan, J.,Abbott, J.,Fesik, S.W. (登録日: 2018-03-26, 公開日: 2019-02-06, 最終更新日: 2023-11-15)

主引用文献

Abbott, J.R.,Patel, P.A.,Howes, J.E.,Akan, D.T.,Kennedy, J.P.,Burns, M.C.,Browning, C.F.,Sun, Q.,Rossanese, O.W.,Phan, J.,Waterson, A.G.,Fesik, S.W.
Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS.
ACS Med Chem Lett, 9:941-946, 2018

PubMed Abstract: Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds that bind to SOS1 and activate nucleotide exchange on RAS. Using structure-based design, we refined the substituents attached to the quinazoline nucleus and built in additional interactions not present in the initial HTS hit. Optimized compounds activate nucleotide exchange at single-digit micromolar concentrations in vitro. In HeLa cells, these quinazolines increase the levels of RAS-GTP and cause signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway.

PubMed: 30258545
DOI: 10.1021/acsmedchemlett.8b00296

実験手法

X-RAY DIFFRACTION (1.833 Å)