Carbamoylphosphonates Inhibit Extracellular Zinc Enzymes in the Tumor Microenvironment

The tumor microenvironment contains certain extracellular zinc enzymes that safeguard the cancer and support its proliferation and dissemination. These water soluble enzymes are (a) matrix metalloproteinase-2 (MMP-2), that degrades basement membrane and opens the way to the dissemination of metastases; (b) carbonic anhydrases (CAIX & XII) that regulate tumor micro-environment pH to support tumor survival; and finally (c) autotaxin, (ATX) that converts lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA) which supports cellular proliferation, tumor growth and metastasis. In view of this hostile microenvironment, scientists are making immense efforts to develop inhibitors to the above mentioned enzymes. We developed water soluble carbamoylphosphonic acid (CPO) inhibitors to maximize their chances to encounter and inhibit the enzymes in the extracellular space, away from cancer or healthy cells.

Our compounds inhibit all three types of enzymes mentioned at similar concentrations. Inhibition of MMP-2 prevents the dissemination of metastases.^[1] Inhibition of CAIX or CAXII modulates the pH of the extracellular fluid disabling the advantage of tumor cells,^[2] or inhibition of ATX stops the generation of LPA and tumor proliferation.^[3] Successful inhibition of these enzymes by CPOs disables cancer and results in a new kind of extracellular, nontoxic antimetastatic & anticancer therapy.

References

[1] J. Frant, A. Veerendhar, T. Chernilovsky, S. Nedvetzki, O. Vaksman, A. Hoffman, E. Breuer, R. Reich, ChemMedChem, 2011, 6, 1471.

[2] R. Reich, A. Hoffman, A. Veerendhar, A. Maresca, A. Innocenti, C.T. Supuran, E. Breuer, J. Med. Chem. 2012, 55, 7875.

[3] Reich, R. Hoffman , A. Suresh , R.R. Shai, O., Frant , J. Maresca, A., Supuran , C.T., Breuer, E. J Enzyme Inhib. Med. Chem., DOI: 10.3109/14756366.2014.968146.