Increase of anti-metastatic efficacy by selectivity- but not affinity-optimization of synthetic serine protease inhibitors

Banke, I. J., Arlt, M. J. E., Pennington, C., Kopitz, C., Steinmetzer, T., Schweinitz, A., Gasbacher, B., Quigley, J. P., Edwards, D. R. ORCID:, Sturzebecher, J. and Kruger, A. (2003) Increase of anti-metastatic efficacy by selectivity- but not affinity-optimization of synthetic serine protease inhibitors. Biological Chemistry, 384 (10-11). pp. 1515-1525.

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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 antimetastatic 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 antimetastatic efficacy. For example, factor Xa inhibitors CJ-504 and CJ-510 exert similar affinity for factor Xa (Ki=14 nM versus 8.8 nM) but CJ-504 was 70-fold more selective for factor Xa. This correlated with higher antimetastatic 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.

Item Type: Article
Faculty \ School: Faculty of Science > School of Biological Sciences
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies
Faculty of Science > Research Groups > Cells and Tissues
Depositing User: EPrints Services
Date Deposited: 01 Oct 2010 13:37
Last Modified: 22 Apr 2023 01:57
DOI: 10.1515/BC.2003.168

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