title: α-Ketobenzothiazole Serine Protease Inhibitors of Aberrant HGF/c-MET and MSP/RON Kinase Pathway Signaling in Cancer.
abstract: Upregulation of the HGF and MSP growth-factor processing serine endopeptidases HGFA, matriptase and hepsin is correlated with increased metastasis in multiple tumor types driven by c-MET or RON kinase signaling. We rationally designed P1' α-ketobenzothiazole mechanism-based inhibitors of these proteases. Structure-activity studies are presented, which resulted in the identification of potent inhibitors with differential selectivity. The tetrapeptide inhibitors span the P1-P1' substrate cleavage site via a P1' amide linker off the benzothiazole, occupying the S3' pocket. Optimized inhibitors display sub-nanomolar enzyme inhibition against one, two, or all three of HGFA, matriptase, and hepsin. Several compounds also have good selectivity against the related trypsin-like proteases, thrombin and Factor Xa. Finally, we show that inhibitors block the fibroblast (HGF)-mediated migration of invasive DU145 prostate cancer cells. In addition to prostate cancer, breast, colon, lung, pancreas, gliomas, and multiple myeloma tumors all depend on HGF and MSP for tumor survival and progression. Therefore, these unique inhibitors have potential as new therapeutics for a diverse set of tumor types.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 S. Euclid Ave., Saint Louis, MO, 63110, USA.
authors.forename: Zhenfu
authors.initials: Z
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 S. Euclid Ave., Saint Louis, MO, 63110, USA.
authors.forename: Peter K W
authors.initials: PK
authors.lastname: Harris
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 S. Euclid Ave., Saint Louis, MO, 63110, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Karmakar
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 S. Euclid Ave., Saint Louis, MO, 63110, USA.
authors.forename: Tommy
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Oncology, Southern Research Institute, 2000 9th Ave., Birmingham, AL, 35205, USA.
authors.forename: Ben Y
authors.initials: BY
authors.lastname: Owusu
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 S. Euclid Ave., Saint Louis, MO, 63110, USA.|Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53792, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Wildman
authors.affiliation: Department of Oncology, Southern Research Institute, 2000 9th Ave., Birmingham, AL, 35205, USA.
authors.forename: Lidija
authors.initials: L
authors.lastname: Klampfer
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 S. Euclid Ave., Saint Louis, MO, 63110, USA. janetkaj@wustl.edu.
authors.forename: James W
authors.initials: JW
authors.lastname: Janetka
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015951:Factor Xa / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; C081092:HGF activator; D012697:Serine Endopeptidases; C055645:hepsin; C485595:matriptase; D013917:Thrombin; D015951:Factor Xa
keywords: cancer; cell signaling; metastasis; serine protease inhibitors; solid-phase peptide synthesis; structure-based drug design