Matrix metalloproteinases (MMPs) have been implicated in tumor development through enhancement of migration, angiogenesis, and metastasis. Therefore, MMP inhibitors (MMPIs) have been described as potential therapeutic agents for cancer treatment. However, clinical development of most MMPIs has been discontinued because of safety reasons due to their low specificity. The design of new MMPIs should pursue not only MMP blockade, but also preserving natural physiological processes that may be jeopardized by inhibition of the wrong class of MMPs. After prolonged research, only MMP1, 2, and 7 have been experimentally validated as cancer targets. On the other hand, reduction of some MMPs such as MMP3, 8, and 9 could enhance tumorigenesis and metastasis, so their inhibition should be avoided.

We describe here the activity of several novel MMPIs generated by computer assisted design and chemical synthesis that present a better inhibitory profile than previous compounds.

Inhibition of MMP2 and 9 activity by increasing concentrations of MMPIs was measured by gelatin zymography using human serum as the source of MMPs. The small molecules were added to the digestion buffer during an overnight incubation and zymogram bands were analyzed by densitometry. Their inhibitory activity was compared to the one elicited by 2R-[(4-biphenylsulfonyl)amino]-N-hydroxy-3-phenylpropinamide (BiPS), a commercially available MMP2/9 inhibitor. Our results show that some molecules inhibit MMP activity more strongly than BiPS, with an IC50 in the picomolar range. Specific MMP2 IC50 values of several of these small molecules were lower than the corresponding values for MMP9, presenting a promising MMP2/MMP9 inhibition ratio.

These inhibitors may be the basis for future therapeutic intervention strategies in cancer.

CompoundIC50 MMP2 (pM)IC50 MMP9 (pM)RATIO MMP9/MMP2
Zr208 741.92 1097.83 1.48 
Zr224 >5.00*103 >50.00*103 
Zr268 9.47 51.47 5.44 
Zr337 1.54 14.87 9.67 
Zr350 2.45 11.11 4.53 
Zr366 7.75 13.57 1.75 
Zr367 10.02 32.69 3.26 
Zr368 1.91 14.63 7.67 
Zr369 325.51 1549.14 4.76 
CompoundIC50 MMP2 (pM)IC50 MMP9 (pM)RATIO MMP9/MMP2
Zr208 741.92 1097.83 1.48 
Zr224 >5.00*103 >50.00*103 
Zr268 9.47 51.47 5.44 
Zr337 1.54 14.87 9.67 
Zr350 2.45 11.11 4.53 
Zr366 7.75 13.57 1.75 
Zr367 10.02 32.69 3.26 
Zr368 1.91 14.63 7.67 
Zr369 325.51 1549.14 4.76 

Calculated IC50 concentrations for MMP2 and MMP9 for several novel molecules

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1553.