title: Increase of anti-metastatic efficacy by selectivity- but not affinity-optimization of synthetic serine protease inhibitors.
abstract: Although tumors frequently show elevated protease activities, the concept of anti-proteolytic cancer therapy has lost momentum after failure of clinical trials with broad-spectrum matrix metalloproteinase inhibitors. Thus we need to adapt our design strategies for protease inhibitors. Here, we employed a series of seven structurally fine-modulated and pharmacokinetically closely related synthetic 4-amidinobenzylamine-based inhibitors with distinct selectivity for prototypical serine proteases in a murine T cell lymphoma liver metastasis model. This in vivo screening revealed efficacy of urokinase inhibitors but no correlation between urokinase selectivity or affinity and anti-metastatic effect. In contrast, factor Xa-selective inhibitors were more potent, demonstrating factor Xa or a factor Xa-like serine protease likely to be more determinant in this model. Factor Xa selectivity, but not affinity, significantly improved anti-metastatic efficacy. For example, factor Xa inhibitors CJ-504 and CJ-510 exert similar affinity for factor Xa (K(i)=14 nM versus 8.8 nM) but CJ-504 was 70-fold more selective for factor Xa. This correlated with higher anti-metastatic efficacy (58.8% with CJ-504; 28.2% with CJ-510). Our results show that among the protease inhibitors employed that have affinities in the nanomolar range, the strategy of selectivity-optimization is superior to further improvement of affinity to significantly enhance anti-metastatic efficacy. This appreciation may be important for the future rational design of new anti-proteolytic agents for cancer therapy.
authors.affiliation: Institut für Experimentelle Onkologie und Therapieforschung, Technische Universität München, Ismaninger Str. 22, D-81675 München, Germany.
authors.forename: Ingo J
authors.initials: IJ
authors.lastname: Banke
authors.forename: Matthias J E
authors.initials: MJ
authors.lastname: Arlt
authors.forename: Caroline
authors.initials: C
authors.lastname: Pennington
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kopitz
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
authors.forename: Andrea
authors.initials: A
authors.lastname: Schweinitz
authors.forename: Bernd
authors.initials: B
authors.lastname: Gansbacher
authors.forename: James P
authors.initials: JP
authors.lastname: Quigley
authors.forename: Dylan R
authors.initials: DR
authors.lastname: Edwards
authors.forename: Jörg
authors.initials: J
authors.lastname: Stürzebecher
authors.forename: Achim
authors.initials: A
authors.lastname: Krüger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000990:Antithrombin III / Q000737:chemistry / Q000378:metabolism; D001596:Benzylamines / Q000138:chemical synthesis / Q000494:pharmacology; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D008113:Liver Neoplasms / Q000201:enzymology / Q000517:prevention & control / Q000556:secondary*; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012697:Serine Endopeptidases / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis* / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D001596:Benzylamines; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D000990:Antithrombin III; D012697:Serine Endopeptidases; C485595:matriptase; C118992:St14 protein, mouse; D014568:Urokinase-Type Plasminogen Activator