title: Identification of selective and potent inhibitors of fibroblast activation protein and prolyl oligopeptidase.
abstract: Fibroblast activation protein (FAP) is a serine protease selectively expressed on reactive stromal fibroblasts of epithelial carcinomas. It is widely believed to play a role in tumor invasion and metastasis and therefore to represent a potential new drug target for cancer. Investigation into its biological function, however, has been hampered by the current unavailability of selective inhibitors. The challenge has been in identifying inhibitors that are selective for FAP over both the dipeptidyl peptidases (DPPs), with which it shares exopeptidase specificity, and prolyl oligopeptidase (PREP), with which it shares endopeptidase specificity. Here, we report the first potent FAP inhibitor with selectivity over both the DPPs and PREP, N-(pyridine-4-carbonyl)-d-Ala-boroPro (ARI-3099, 6). We also report a similarly potent and selective PREP inhibitor, N-(pyridine-3-carbonyl)-Val-boroPro (ARI-3531, 22). Both are boronic acid based inhibitors, demonstrating that high selectivity can be achieved using this electrophile. The inhibitors are stable, easy to synthesize, and should prove to be useful in helping to elucidate the biological functions of these two unique and interesting enzymes, as well as their potential as drug targets.
authors.affiliation: Department of Biochemistry, Tufts University Sackler School of Biomedical Sciences, 136 Harrison Avenue, Boston, Massachusetts 02111, United States.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Poplawski
authors.forename: Jack H
authors.initials: JH
authors.lastname: Lai
authors.forename: Youhua
authors.initials: Y
authors.lastname: Li
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Jin
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Liu
authors.forename: Wengen
authors.initials: W
authors.lastname: Wu
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhou
authors.forename: James L
authors.initials: JL
authors.lastname: Sudmeier
authors.forename: David G
authors.initials: DG
authors.lastname: Sanford
authors.forename: William W
authors.initials: WW
authors.lastname: Bachovchin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001897:Boronic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D055808:Drug Discovery; D010450:Endopeptidases; D018093:Gelatinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D011392:Proline / Q000378:metabolism; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D001897:Boronic Acids; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D011392:Proline; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D000099167:Fibroblast Activation Protein Alpha; C000705287:PREPL protein, human