NSC 658497

NSC-658497 is an effective inhibitor of Ras-GEF, SOS1. NSC-658497 binds to SOS1, competitively suppresses SOS1-Ras interaction, and dose-dependently inhibits SOS1 GEF activity. NSC-658497 showed dose-dependent efficacy in inhibiting Ras, downstream signaling activities, and associated cell proliferation[1].

Research Areas >> Cancer

Signaling Pathways >> GPCR/G Protein >> Ras

NSC-658497 (0-20 μM; 2 hours; NIH/3T3 cells) dose-dependently inhibits EGF (50 ng/mL)-stimulated Ras, but not EGFR activation[1]. Concomitant to Ras inhibition, NSC-658497 (0-100 μM; 2 hours; NIH/3T3 cells) dose-dependently inhibited the EGF activated, Ras downstream targets ERK1/2 and AKT[1]. Consistent with these results, NSC-658497 dose-dependently suppressed Ras signaling mediated by the overexpression of an active SOS1 mutant (W729L), originally identified in Noonan’s Syndrome, in human embryonic kidney cells[1]. NSC-658497 dose-dependently inhibits 50 nM SOS1-cat mediated GDP/GTP nucleotide exchange upon 2 μM H-Ras (aa. 1-166) in the BODIPYFL-GDP dissociation assay (IC50=15.4μM)[1]. NSC-658497 (0-60 μM; 3 days; PC-3 and DU-145 cells) inhibits proliferation of prostate cancer cells[1]. NSC-658497 (0-60 μM; 2 hours; PC-3 and DU-145 cells) dose-dependently inhibits Ras-GTP activity and the downstream p-ERK1/2 and p-Akt activities[1]. Cell Proliferation Assay[1] Cell Line: PC-3 and DU-145 cells Concentration: 0-60 μM Incubation Time: 3 days Result: Dose-dependently inhibited proliferation of PC-3 and DU-145 cells. Western Blot Analysis[1] Cell Line: PC-3 and DU-145 cells Concentration: 0-60 μM Incubation Time: 2 hours Result: Dose-dependently inhibited Ras-GTP activity and the downstream p-ERK1/2 and p-Akt activities.

[1]. Evelyn CR, et al. Rational design of small molecule inhibitors targeting the Ras GEF, SOS1. Chem Biol. 2014;21(12):1618-1628.