The definition of repurposing in the context of drug discovery encompasses a variety of strategies designed to redirect current therapeutic knowledge towards new disease indications. This approach can be successful for the design of new drugs to treat diseases of the developing world such as Malaria, where there are limited resources to fund new drug discovery campaigns. Moreover, it can be used to decrease the drug development time for diseases in which there is high drug attrition rates coupled with high mortality rates, which is the case for some cancers.
To this end, two separate medicinal chemistry projects are presented herein which are both based on current drug scaffolds originally used for alternative therapeutic indications. The first is the design of an inhibitor of Plasmodium Falciparum Myosin A (PfMyoA), a motor protein implicated in the blood stage invasion of Malaria. Structural predictions of the myosin structure have been made in the form of a homology model using the crystal structure of a well characterised homologue, myosin II and its inhibitor, (S)-Blebbistatin. Plasmodium specific inhibitors were designed in silico based on the structure of (S)-Blebbistatin and synthesised for validation of the model using biological testing of their effect on myosin activity and importantly, on parasite invasion. Interestingly, compounds were found to reduce parasitaemia in red blood cells, independently of PfMyoA, suggesting interaction with an alternative essential myosin.
The second project described is the synthesis of compounds that inhibit 90-kDa ribosomal S6 kinase 4 (RSK4), a promotor of lung cancer metastasis and resistance to chemotherapeutic treatments. Inhibitors were synthesised based on the structures of fluoroquinolone antibiotics Moxifloxacin and Trovafloxacin which were identified as moderately potent inhibitors of RSK4. Derivatives were designed with enhanced solubility and tested in a cell-based assay in which 10 novel compounds were identified that inhibit RSK4 activation by at least 50%.