Anthraquinones as Inhibitors of SOS RAS-GEF Activity

Recent breakthroughs have reignited interest in RAS GEFs as direct therapeutic targets. To search for new inhibitors of SOS GEF activity, a repository of known/approved compounds (NIH-NACTS) and a library of new marine compounds (Biomar Microbial Technologies) were screened by means of in vitro RAS-GEF assays using purified, bacterially expressed SOS and RAS constructs. Interestingly, all inhibitors identified in our screenings (two per library) shared related chemical structures belonging to the anthraquinone family of compounds. All our anthraquinone SOS inhibitors were active against the three canonical RAS isoforms when tested in our SOS GEF assays, inhibited RAS activation in mouse embryonic fibroblasts, and were also able to inhibit the growth of different cancer cell lines harboring WT or mutant RAS genes. In contrast to the commercially available anthraquinone inhibitors, our new marine anthraquinone inhibitors did not show in vivo cardiotoxicity, thus providing a lead for future discovery of stronger, clinically useful anthraquinone SOS GEF blockers.

Automated summary

The study found that new inhibitors of the anthraquinone family shared related chemical structures and were able to target multiple RAS isoforms, inhibit RAS activation in cells, and suppress the growth of cancer cell lines with different RAS genes. Unlike commercially available anthraquinone inhibitors, the new marine anthraquinone inhibitors did not exhibit cardiotoxicity, suggesting their potential as stronger and clinically useful blockers of anthraquinone SOS GEF.