Franco, Francisco M. published the artcileStructure-based discovery of small molecule hepsin and HGFA protease inhibitors: Evaluation of potency and selectivity derived from distinct binding pockets, Computed Properties of 478646-32-1, the main research area is structure hepsin HGFA protease inhibitor; Benzamidine; Cancer; Cell-signaling; Enzyme inhibitor; Growth factor; HGF; HGFA; Hepsin; MSP; Matriptase; Peptidomimetic; RON; Receptor tyrosine kinase; Serine protease; Small-molecule; Structure-based drug design; Therapeutic; c-MET.
Hepatocyte growth factor activator (HGFA), matriptase and hepsin are all S1 trypsin-like serine endopeptidases. HGFA is a plasma protease while hepsin and matriptase are type II transmembrane proteases (TTSPs). Upregulated expression and activity of all three proteases is associated with aberrant cancer cell signaling through c-MET and RON tyrosine kinase cell-signaling pathways in cancer. The authors modeled known benzamidine protease inhibitor scaffolds into the active sites of matriptase, hepsin and HGFA to design new nonpeptide inhibitors of hepsin and HGFA. First, the authors used a docking model of the irreversible inhibitor, Nafamostat, bound to the active site of HGFA in order to explore structure activity relationships (SAR). Compounds were screened for inhibition of HGFA activity in a kinetic enzyme assay using a chromogenic substrate. Next, the authors designed matched pair compound libraries of 3-amidino and 4-amidino phenylalanine (benzamidine) arginine peptidomimetics based on the structure of matriptase inhibitor, CJ-672. Compounds were screened for inhibition of HGFA, matriptase, and hepsin enzyme activity using fluorogenic substrates. Using this strategy the authors have discovered the first reported nonpeptide small mol. inhibitors of both HGFA and hepsin. These inhibitors have differential potency and selectivity towards all three proteases. A subset of piperazinyl ureas highlighted by I, have excellent potency and selectivity for hepsin over matriptase and HGFA.
Bioorganic & Medicinal Chemistry published new progress about Homo sapiens. 478646-32-1 belongs to class piperidines, name is (R)-Benzyl piperidin-3-ylcarbamate, and the molecular formula is C13H18N2O2, Computed Properties of 478646-32-1.
Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem