Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS

Area of Science:

• Molecular Biology
• Medicinal Chemistry
• Oncology

Background:

• RAS proteins are key regulators of cellular signaling, and their mutations are implicated in cancer.
• Targeting RAS proteins directly has been challenging, necessitating alternative strategies like targeting interacting proteins.
• Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor (GEF) that interacts with RAS.

Purpose of the Study:

• To report hit-to-lead studies on quinazoline-containing compounds designed to inhibit SOS1 activity.
• To develop novel therapeutic agents that modulate RAS signaling by targeting SOS1.
• To investigate the in vitro and cellular effects of optimized quinazoline compounds on RAS-GTP levels and downstream signaling.

Main Methods:

• Structure-based design was employed to refine quinazoline compounds targeting SOS1.
• Hit-to-lead optimization involved modifying substituents on the quinazoline nucleus to enhance interactions.
• In vitro assays were used to measure nucleotide exchange activation on RAS, and cellular studies in HeLa cells assessed RAS-GTP levels and MAPK/ERK pathway activation.

Main Results:

• Optimized quinazoline compounds demonstrated activation of nucleotide exchange on RAS at single-digit micromolar concentrations in vitro.
• Cellular studies showed that these quinazolines increased RAS-GTP levels in HeLa cells.
• Treatment with the compounds led to observable signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway.

Conclusions:

• Quinazoline-based compounds effectively target SOS1 and modulate RAS signaling.
• The developed compounds show potential as therapeutic agents for cancers driven by RAS pathway dysregulation.
• Further investigation into these SOS1 modulators could lead to novel cancer therapies.