hIRG1 medicinal chemistry effort

Division Of Basic Sciences - Nci

Investigators

Abstract

In FY2025 we achieved several of the objectives listed. Specifically, we obtained the structure of hIRG in its true empty form (devoid of any non-specific inhibitor molecules that were appearing from crystallization cocktails) and a long sought-after inhibited structure in the presence of citraconate. The structures were obtained at very high resolution. We also developed and validated a novel assay based on nuclear magnetic resolnance. This assay uses less protein than previous iterations while giving full activity curves as it is a non-destructive, continuous assay. We have submitted a pre-print with these findings to the public domain and are in the process of submitting a full article for peer-review. We are continuing the project focusing on novel inhibitors discovered in high-throughput assays (performed at the Molecular Targets Program). This enzyme is challenging as it has specific dynamics involved in binding and inhibition. The new inhibitors have been shown effective in initial activity assays, but their structural-base for inhibition is still unknown. We are also pursuing structural and mutational studies to elucidate the enzymatic mechanism further and will be initiating a high-throughput fragment screen in FY2026.