Abstract:
Cancer is a disease that is a "moving target", since as the condition progresses, the molecular targets change and evolve. Moreover, due to clonal selection, a specific anti-cancer drug with one molecular target may only be effective for a limited time period before drug resistance results and the agent becomes ineffective. Hence, the concept of an anti-tumor therapeutic exhibiting polypharmacology can be highly advantageous, rather than a therapeutic obstacle.
A novel class of agents possessing these desirable properties are the di-2-pyridylketone thiosemicarbazones, which bind iron and copper to affect a variety of critical molecular targets in tumors. In fact, these compounds possess multiple properties that enable them to overcome the "triad of death" in cancer, namely: primary tumor growth, drug resistance, and metastasis.
Currently, there are no drugs to treat the spread of the cancer (metastasis), despite that it kills 90% of cancer patients. The current agents were developed and patented over a period of 30 years of intensive structure-activity relationship studies. The agents possess an innovative mechanism of anti-tumor activity with a key activity being the ability to up-regulate a potent metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1).
Through multiple mechanisms including the induction of NDRG1, these agents induce up-regulation of the tumor suppressors, PTEN and MIG6; down-regulation of the proto-oncogene, cyclin D1; inhibition of the rate-limiting step in DNA synthesis catalyzed by ribonucleotide reductase; and the inhibition of multiple oncogenic signaling pathways, e.g., Ras/MAPK signaling, protein kinase B (AKT)/phosphatidylinositol-3-kinase, ROCK/pMLC2, etc.
This presentation will discuss the advantages of incorporating polypharmacology into anti-cancer drug design using the di-2-pyridylketone thiosemicarbazones as a pertinent example.