Increase of Anti-Metastatic Efficacy by Selectivity- But Not Affinity-Optimization of Synthetic Serine Protease Inhibitors
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| 024 | 7 | 0 | |a 10.1515/BC.2003.168 |2 doi |
| 035 | |a (NATIONALLICENCE)gruyter-10.1515/BC.2003.168 | ||
| 245 | 0 | 0 | |a Increase of Anti-Metastatic Efficacy by Selectivity- But Not Affinity-Optimization of Synthetic Serine Protease Inhibitors |h [Elektronische Daten] |c [I. J. Banke, M. J. E. Arlt, C. Pennington, C. Kopitz, T. Steinmetzer, A. Schweinitz, B. Gansbacher, J. P. Quigley, D. R. Edwards, J. Stürzebecher, A. Krüger] |
| 520 | 3 | |a 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. | |
| 540 | |a Copyright © 2003 by Walter de Gruyter GmbH & Co. KG | ||
| 690 | 7 | |a Biochemistry |2 nationallicence | |
| 690 | 7 | |a Molecular biology |2 nationallicence | |
| 690 | 7 | |a Cellular biology |2 nationallicence | |
| 700 | 1 | |a Banke |D I. J. |4 aut | |
| 700 | 1 | |a Arlt |D M. J. E. |4 aut | |
| 700 | 1 | |a Pennington |D C. |4 aut | |
| 700 | 1 | |a Kopitz |D C. |4 aut | |
| 700 | 1 | |a Steinmetzer |D T. |4 aut | |
| 700 | 1 | |a Schweinitz |D A. |4 aut | |
| 700 | 1 | |a Gansbacher |D B. |4 aut | |
| 700 | 1 | |a Quigley |D J. P. |4 aut | |
| 700 | 1 | |a Edwards |D D. R. |4 aut | |
| 700 | 1 | |a Stürzebecher |D J. |4 aut | |
| 700 | 1 | |a Krüger |D A. |4 aut | |
| 773 | 0 | |t Biological Chemistry |d Walter de Gruyter |g 384/10-11(2003-11-07), 1515-1525 |x 1431-6730 |q 384:10-11<1515 |1 2003 |2 384 |o bchm | |
| 856 | 4 | 0 | |u https://doi.org/10.1515/BC.2003.168 |q text/html |z Onlinezugriff via DOI |
| 908 | |D 1 |a research article |2 jats | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1515/BC.2003.168 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Banke |D I. J. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Arlt |D M. J. E. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Pennington |D C. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Kopitz |D C. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Steinmetzer |D T. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Schweinitz |D A. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Gansbacher |D B. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Quigley |D J. P. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Edwards |D D. R. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Stürzebecher |D J. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Krüger |D A. |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Biological Chemistry |d Walter de Gruyter |g 384/10-11(2003-11-07), 1515-1525 |x 1431-6730 |q 384:10-11<1515 |1 2003 |2 384 |o bchm | ||
| 900 | 7 | |b CC0 |u http://creativecommons.org/publicdomain/zero/1.0 |2 nationallicence | |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-gruyter | ||