Targeting methionine aminopeptidase 2 in cancer, obesity, and autoimmunity

Spanning decades, pharmacological inhibition of methionine aminopeptidase 2 (MetAP2) has been pursued to treat diseases including cancer, obesity, and inflammatory diseases. Irreversible MetAP2 inhibitors have consistently failed in clinical trials due either lack efficacy or side effects undermining efficacy, some which may be off-target activity. Limited information regarding mode action a consistency between applications drug development efforts hindered the progress inhibitors. Mechanistic insight into inhibitor action, particularly clear understanding substrates driving will guide safe application human disease. For over three tentative target for treatment autoimmune Currently, no (MetAP2i) reached clinic yet, despite considerable investment by major pharmaceutical companies. Here, we summarize key series MetAP2i developed date discuss their development, progress, issues. We coalesce currently disparate knowledge mechanism discrepancies across varied studies. Finally, highlight current gaps that need addressed enable successful settings. physiological process new blood vessels are formed from preexisting vessels, also plays an important role supplying nutrients oxygen cancer progression metastasis. biotin is known as vitamin B7 involved normal cell homeostasis. However, biochemical applications, it widely used its strong interaction with streptavidin, allowing efficient enrichment biotinylated compounds molecules affinity purification. highly vascularized membrane found avian eggs; robust experimental platform study angiogenesis relation research development. chemical compound cellular component inhibits growth; specifically, does not imply require cytotoxicity. negatively affects viability (i.e., toxic cells). initiator resulting start codon (typically AUG); first residue all proteins eukaryotes, except certain organelle-produced where formylmethionine, occurs prokaryotes. umbilical vein endothelial cells; primary cells model most experiments studying cytostatic effect MetAP2i. lipophilic ligand efficiency; parameter discovery links potency (IC50) lipophilicity (logP), serving estimate quality developability. LLE = pIC50 – logP, such high values considered quality. blanket term referring routes administration oral, typically involving injection different types tissues. The set signalling cascades initiated binding Wnt frizzled family receptors. canonical pathway Wnt/β-catenin characterised accumulation intracellular β-catenin translocation nucleus, regulates gene expression genes direct transcription factors. Noncanonical pathways defined other receptors do lead β-catenin. These well but generally divided two categories: Wnt/Ca2+ Wnt/planar polarity (PCP), depending on mediators final responses activated. described affect through NFAT factor family, while Wnt/PCP leads cytoskeletal rearrangement adjustments promotes survival [91.Ackers I. Malgor R. Interrelationship non-canonical chronic metabolic diseases.Diabetes Vasc. Dis. Res. 2018; 15: 3-13Crossref PubMed Scopus (59) Google Scholar].