Analyses of ligand binding and potential inhibitors of SHMT2

Abstract

The serine hydroxymethyltransferase-2 enzyme (SHMT2) catalyses the conversion of serine to glycine and produces one-carbon units essential for DNA biosynthesis (purine and thymidine). SHMT2 expression was found to be significantly upregulated in cancers (liver, pancreas, and breast cancer) to support cancer cell growth and proliferation. SHMT2 is a key enzyme of the one-carbon metabolism (1CM) pathway that has not yet been targeted clinically. Also, it was found that SHMT2 dimers regulate inflammatory cytokine signalling through interaction with the BRISC deubiquitylase complex. Here, we hypothesised that pre-selected compounds from a docking study to target the PLP pocket can bind and promote SHMT2 tetramerization. The SHMT2-ligand interaction was tested using differential scanning fluorimetry and mass photometry. The SHMT2 oligomeric transition was induced in the presence of compounds 12A, 12, and 9A at concentrations greater than 10 µM. Our findings provide insights into starting points for SHMT2 inhibitors that could eventually mature to candidate lead compounds for SHMT2 functional studies in disease.