The prince and the pauper. A tale of anticancer targeted agents

Abstract

Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationallybased designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single publicsector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited public-sector resources. If these drug types eventually result in being effective, it follows that they could be much more affordable for patients with cancer; therefore, their contribution in terms of reducing cancer mortality at the global level would be greater.

Nicotinamide sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin

“…Nevertheless, cancer drug development needs alternative approaches for drug identification because of increasing failure rates, high cost, poor safety, limited efficacy, and a lengthy design and testing process of new entities. In this sense, drug repurposing of established non-cancer drugs that have anticancer activity provides an opportunity to rapidly advance therapeutic strategies in clinical trials (9,10).…”

“…Repurposing existing drugs is another strategy for drug development in which safety pharmacology studies have been already done, which reduces the time and cost of approving the compounds for clinical use (9,10). Nicotinamide (NAM; pyridine-3-carboxylic acid) is a water-soluble amide active form of vitamin B3 or niacin.…”

Homology modeling, docking and structure-based pharmacophore of inhibitors of DNA methyltransferase

“…Using a drug repurposing strategy [73], clinical trials have demonstrated the antitumor effect of the combination of hydralazine with valporic acid (a histone deacetylase inhibitor) [74]. Figure 5a shows the comparison of the binding modes of hydralazine with 5-azacytidine.…”

Drug repositioning and repurposing: terminology and definitions in literature

“…In addition to the five terms searched for in PubMed, six other terms were identified that were used as synonyms of drug repositioning namely: 'drug re-tasking' [19,20], 'indication switching' [21], 'indication switch' [22], 'therapeutic switching' [19,23], 'indication expansion' [20], 'candidate or compound repurposing' [24]. The terms 'in silico drug repositioning' [15,25,26], 'on-target repositioning' and 'off-target repositioning' [27] were used as a further specification of drug repositioning.…”