Targeting Glutaminase with RP10107: A Promising Therapeutic Approach for Solid Tumors

RP10107 is a newly developed small molecule inhibitor of glutaminase (GLS1), an enzyme that plays a critical role in cancer cell metabolism. The compound has shown promise as a potential therapeutic agent for solid tumors by targeting the Warburg effect, where cancer cells produce lactate even in the presence of oxygen.

The inhibitory activity of RP10107 against GLS1 was evaluated in rodent brain lysates and recombinant human enzyme preparations, demonstrating high potency with IC50 values in the nanomolar range. Importantly, RP10107 displayed selectivity for GLS1 over liver glutaminase (GLS2), with minimal inhibition of GLS2 even at higher concentrations.

In cellular assays using breast, lung, and colorectal cancer cell lines, RP10107 induced a dose-dependent decrease in cell proliferation, with the most pronounced effect observed in MDA-MB-231 cells. The compound also led to a dose-dependent increase in the glutamine to glutamate ratio, indicating its effect on glutaminase activity. Additionally, RP10107 treatment resulted in a reduction of cMyc and pS6 expression levels in lung and breast cancer cells, without affecting p-mTOR.

Pharmacokinetic studies in mice showed that RP10107 has high oral bioavailability and achieves maximum plasma concentrations exceeding 10 μM. The compound's efficacy and pharmacokinetic profile suggest its potential as a clinical candidate for solid tumors.

In conclusion, RP10107 is a potent and selective GLS1 inhibitor that has demonstrated the ability to inhibit the growth of various solid tumor cell lines and modulate key oncogenic pathways. The compound is currently being evaluated in mouse xenograft models to further assess its antitumor activity.