1201581-67-0Relevant articles and documents
Novel reversible methionine aminopeptidase-2 (MetAP-2) inhibitors based on purine and related bicyclic templates
Heinrich, Timo,Buchstaller, Hans-Peter,Cezanne, Bertram,Rohdich, Felix,Bomke, J?rg,Friese-Hamim, Manja,Krier, Mireille,Kn?chel, Thorsten,Musil, Djordje,Leuthner, Birgitta,Zenke, Frank
, p. 551 - 556 (2017/01/17)
The natural product fumagillin 1 and derivatives like TNP-470 2 or beloranib 3 bind to methionine aminopeptidase 2 (MetAP-2) irreversibly. This enzyme is critical for protein maturation and plays a key role in angiogenesis. In this paper we describe the synthesis, MetAP-2 binding affinity and structural analysis of reversible MetAP-2 inhibitors. Optimization of enzymatic activity of screening hit 10 (IC50: 1?μM) led to the most potent compound 27 (IC50: 0.038?μM), with a concomitant improvement in LLE from 2.1 to 4.2. Structural analysis of these MetAP-2 inhibitors revealed an unprecedented conformation of the His339 side-chain imidazole ring being co-planar sandwiched between the imidazole of His331 and the aryl-ether moiety, which is bound to the purine scaffold. Systematic alteration and reduction of H-bonding capability of this metal binding moiety induced an unexpected 180° flip for the triazolo[1,5-a]pyrimdine bicyclic template.
