A practical approach for the synthesis of lactate dehydrogenase A inhibitor GNE-140

Abstract

GNE-140 is the first lactate dehydrogenase A (LDHA) inhibitor that demonstrates both sub-micromolar cellular potency and adequate pharmacokinetic properties, making it suitable for in vivo applications as a tool compound. However, the synthetic route reported by Genentech is complex, relying on transition metal catalysis and yielding low overall amounts. This study presents a practical, scalable method for constructing the core six-membered ring and quaternary carbon center of GNE-140 without transition metal catalysis, achieving a 48.5% racemic yield in a seven-step sequence, paving the way for future LDHA inhibitor development.