Congratulations to Dr Andrea Goya Grocin and Dr Wouter Kallemeijn on their publication

For over three decades, methionine aminopeptidase 2 (MetAP2) has been a sought-after drug target for the potential treatment of cancer, obesity, and autoimmune diseases. Over ten distinct MetAP2 inhibitor series have been described to date, including both covalent and reversible binders. However, no drug targeting MetAP2 (MetAP2i) has yet reached approval, despite considerable investment by several major pharmaceutical companies.

Despite these extensive drug development efforts, scientific understanding of MetAP2i mode-of-action is surprisingly limited. MetAP2i are strikingly well-tolerated in patients with little or no toxicity at therapeutically relevant doses, and have been developed for impressively diverse pharmacological applications, but there is currently no mechanistic link between these applications beyond MetAP2 as the putative target.

In this review, Andrea and Wouter summarize the key MetAP2 inhibitor series developed to date, and highlight their clinical development, including several important clinical trial failures. They assemble and rationalise the diverse mechanistic knowledge across the medicinal chemistry literature, and discuss key discrepancies and knowledge gaps that need to be addressed to enable future success of MetAP2i in clinical settings.