Abstract
Drug repurposing is a method of drug discovery that consists of finding a new therapeutic context for an old drug. Compound identification arises from screening of large libraries of active compounds, through interrogating databases of cell line gene expression response upon treatment or by merging several types of information concerning disease–drug relationships. Although, there is a general consensus on the potential and advantages of this drug discovery modality, at the practical level to-date no non-anti-cancer repurposed compounds have been introduced into standard acute myeloid leukaemia (AML) management, albeit that preclinical validation yielded several candidates. The review presents the state-of-the-art drug repurposing approach in AML and poses the question of what has to be done in order to take a full advantage of it, both at the stage of screening design and later when progressing from the preclinical to the clinical phases of drug development. We argue that improvements are needed to model and read-out systems as well as to screening technologies, but also to more funding and trust in drug repurposing strategies.
Highlights
What Is Drug Repurposing?Drug repurposing, or its variant-drug repositioning, is an attractive drug discovery approach whereby the exploitation of an already-approved or investigational drug for a new therapeutic indication is attempted [1,2,3,4]
Clofarabine, a purine nucleoside antimetabolite structurally related to cladribine, is a case of soft repurposing as it was initially approved by the Food and Drug Administration (FDA) for the treatment of children with relapsed or refractory acute lymphoblastic leukaemia (ALL) [29]
A psychotropic drug, demonstrated potential for being repurposed in acute myeloid leukaemia (AML) treatment as it is able to inhibit the phosphorylation of the STAT5 transcription factor that is crucial for proliferation of leukaemic cells with FLT3-ITD mutation, resulting in cell death in vitro and in vivo [55]
Summary
Its variant-drug repositioning, is an attractive drug discovery approach whereby the exploitation of an already-approved or investigational drug for a new therapeutic indication is attempted [1,2,3,4]. Novel methods to recognize potential drugs to be repurposed are being developed and are indispensable (examples reviewed in [6,7]) Both experimental and computational repurposing approaches can be used. A drug can elicit the desired pharmacological effect at concentrations that are higher than those used in the “old” therapeutic setting or reach anti-cancer effects only in combination with existing chemotherapeutic/new repurposed agents In such cases, a new evaluation of absorption, distribution, metabolism, excretion, toxicity and side effects, should be performed [20]. No financial incentives to carry out clinical trials of drugs to be repurposed exist; there is no pressure for official approval, no market authorization or inclusion in clinical practice resulting in damage to public health and cancer patients. The review presents the state-of-the-art drug repurposing approach in acute myeloid leukaemia (AML), analyses development times and poses the question of how to exploit this approach, both at the stage of screening design and later when progressing from the preclinical to the clinical phases of drug discovery
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