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CRYSTAL STRUCTURE OF HUMAN METHIONINE AMINOPEPTIDASE-2 IN COMPLEX WITH AN INHIBITOR Thiophene-2-sulfonic acid (4-fluoro-benzyl)-(4H-[1,2,4]triazol-3-ylmethyl)-amide
Structural highlights
FunctionMAP2_HUMAN Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). The catalytic activity of human METAP2 toward Met-Val peptides is consistently two orders of magnitude higher than that of METAP1, suggesting that it is responsible for processing proteins containing N-terminal Met-Val and Met-Thr sequences in vivo. Protects eukaryotic initiation factor EIF2S1 from translation-inhibiting phosphorylation by inhibitory kinases such as EIF2AK2/PKR and EIF2AK1/HCR. Plays a critical role in the regulation of protein synthesis. Publication Abstract from PubMedCo- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth suggesting that small molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure-based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the liphophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from a HTS campaign 11a was discovered with an enzymatic IC50 of 150 nM. The re-synthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC50 of 1.9 microM. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC50 of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and anti-tumor efficacy which led to the identification of advanced lead 21. Discovery and Structure-Based Optimization of Next Generation Reversible Methionine Aminopeptidase-2 (MetAP-2) Inhibitors.,Heinrich T, Seenisamy J, Blume B, Bomke J, Calderini M, Eckert U, Friese-Hamim M, Kohl R, Lehmann M, Leuthner B, Musil D, Rohdich F, Zenke FT J Med Chem. 2019 Apr 2. doi: 10.1021/acs.jmedchem.9b00041. PMID:30939017[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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