The repositioning or “repurposing” of existing therapies for alternative disease indications is an attractive approach that can save significant investments of time and money during drug development. For cancer indications, the primary goal of repurposed therapies is on efficacy, with less restriction on safety due to the immediate need to treat this patient population. This report provides a high-level overview of how drug developers pursuing repurposed assets have previously navigated funding efforts, regulatory affairs, and intellectual property laws to commercialize these “new” medicines in oncology. This article provides insight into funding programs (e.g., government grants and philanthropic organizations) that academic and corporate initiatives can leverage to repurpose drugs for cancer. In addition, we highlight previous examples where secondary uses of existing, Food and Drug Administration- or European Medicines Agency-approved therapies have been predicted in silico and successfully validated in vitro and/or in vivo (i.e., animal models and human clinical trials) for certain oncology indications. Finally, we describe the strategies that the pharmaceutical industry has previously employed to navigate regulatory considerations and successfully commercialize their drug products. These factors must be carefully considered when repurposing existing drugs for cancer to best benefit patients and drug developers alike.

Signal transducer and activator of transcription protein 3 (STAT3) is a latent cytosolic transcription factor that is widely recognized as being a master regulator of the cellular functions that lead to the cancer phenotype. Constitutively activated STAT3 protein activity is routinely observed in human cancers, promoting uncontrolled cell proliferation and suppressing apoptosis. Until relatively recently, inhibition of STAT3 transcriptional activity was achieved indirectly via suppression of upstream kinase activators and extracellular cytokine and (or) growth factor stimuli. However, activated STAT3 forms transcriptionally functional STAT3-STAT3 dimers, providing a valid juncture for targeted downstream molecular inhibition. STAT3's prominent role in cancer has seen a decade of innovative and novel approaches to targeting constitutively active STAT3 protein-protein complexes. This mini-review outlines the progress made towards identifying molecular agents capable of silencing aberrant STAT3 signalling through the disruption of STAT3 complexation events.

Signal transducer and activator of transcription 3 (Stat3) protein is a cytosolic transcription factor that relays signals from receptors in the plasma membrane directly to the nucleus, and is routinely hyperactivated in many human cancers and diseases. [1] Regarded as an oncogene, Stat3 is well-recognized as a master regulator of cellular events that lead to the cancer phenotype, making this protein viable target for molecular therapeutic design. [2] Stat3 inhibitors have included peptides, [3][4] peptidomimetics, [5][6][7][8][9] small molecules [10][11][12][13][14] and metal complexes.[15] Despite significant advances in Stat3 inhibition, [1] truly potent (in vivo), isoform-selective, small molecule Stat3 agents have not been readily forthcoming; this is likely due in part to the challenge of disrupting protein-protein interactions. [16] The canonical view of Stat3 signaling describes inactive Stat3 monomers located predominantly within the cytoplasm. The Stat3 activation pathway begins with a cytokine or growth factor ligand interaction with the extracellular domain of a transmembrane receptor. Subsequently, receptor-associated tyrosine kinases such as the Janus kinases (Jaks) are induced to phosphorylate tyrosine residues on the specific receptor's cytoplasmic domain. These phosphorylated residues then serve to recruit latent Stat monomers through interaction with their SH2 domains. Tyrosine-kinase-mediated phosphorylation of Tyr705 on Stat3 monomers induces Stat3-receptor dissociation and Stat3-Stat3 homodimerization through reciprocal phosphotyrosine (pTyr)-SH2 domain interactions. The resulting transcriptionally active Stat3 dimers then translocate to the nucleus, where they bind to specific DNAresponse elements in the promoters of target genes and induce antiapoptotic gene expression programs (e.g., Bcl-x L ) and the overexpression of cell cycle regulators (for example, cyclin D 1 ).[17] Current programs of research, including our own, have focused on inhibiting the Correspondence to: Patrick T. Gunning, patrick.gunning@utoronto.ca. NIH Public Access Author ManuscriptChembiochem. Author manuscript; available in PMC 2010 August 10. Figure 1A; IC 50 = 86 μM) through in silico structure-based virtual screening of National Cancer Institute chemical libraries.[12] We sought to optimize lead agent S3I-201 through rational, synthetic modifications with the global objective of obtaining isoform-selective, Stat3 inhibitors displaying potency at low to submicromolar concentrations. S3I-201 is based on a glycolic acid scaffold whose carboxylic acid functionality has been condensed with 4-aminosalicylic acid to furnish the amide bond, and whose hydroxyl has been tosylated ( Figure 1A). The Stat3 SH2 domain is broadly composed of three subpockets, but GOLD [18] docking studies showed that S3I-201 can access only two of these subpockets simultaneously ( Figure 1B), and this identified a potential means of improving inhibitor potency. The salicylic (ortho-hydroxybenzoic) acid component of S3I-201 is a known pTyr ...

Cystic Fibrosis (CF) is caused by mutations in the CFTR gene, of which over 2000 have been reported to date. Mutations have yet to be analyzed in aggregate to assess their distribution across the tertiary structure of the CFTR protein, an approach that could provide valuable insights into the structure-function relationship of CFTR. In addition, the binding site of Class I correctors (VX-809, VX-661, and C18) is not well understood. In this study, exonic CFTR mutations and mutant allele frequencies described in 3 curated databases (ABCMdb, CFTR1, and CFTR2, comprising >130 000 data points) were mapped to 2 different structural models: a homology model of full-length CFTR protein in the open-channel state, and a cryo-electron microscopy core-structure of CFTR in the closed-channel state. Accordingly, residue positions of 6 high-frequency mutant CFTR alleles were found to spatially co-localize in CFTR protein, and a significant cluster was identified at the NBD1:ICL4 interdomain interface. In addition, immunoblotting confirmed the approximate binding site of Class I correctors, demonstrating that these small molecules act via a similar mechanism in vitro, and in silico molecular docking generated binding poses for their complex with the cryo-electron microscopy structure to suggest the putative corrector binding site is a multi-domain pocket near residues F374-L375. These results confirm the significance of interdomain interfaces as susceptible to disruptive mutation, and identify a putative corrector binding site. The structural pharmacogenomics approach of mapping mutation databases to protein models shows promise for facilitating drug discovery and personalized medicine for monogenetic diseases.