Poster Presentation First Malaria World Congress 2018

Repurposing cancer drugs - a new perspective for antimalarial drug discovery? (#310)

Simona John von Freyend 1 , Jack D Adderley 1 , Sarah Jackson 1 , Amy L Burns 2 , Anja Ruether 3 , Anna Sexton 4 , Darren Creek 4 , Bayden Wood 3 , Danny Wilson 2 , Christian Doerig 1
  1. Monash Biomedicine Discovery Institute and Department of Microbiology , Monash University, Melbourne, Victoria, Australia
  2. Research Centre for Infectious Diseases, School of Biological Sciences , University of Adelaide,, Adelaide, South Australia, Australia
  3. Centre for Biospectroscopy and School of Chemistry , Monash University , Melbourne, Victoria, Australia
  4. Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia

 

There is an urgent need for new antimalarial drugs with untapped modes of action. The repurposing of approved drugs that hit human targets, or of compounds that have successfully passed the early several phases of clinical trials, would be an ideal strategy to (i) hit novel targets, thus avoiding cross-resistance to existing antimalarials, (ii) deprive the parasite of the fasted mechanism for resistance (since the target will not be encoded by the parasite’s genome), and (iii) circumvent cost and time requirements of drug discovery.

With this purpose in mind our laboratory is exploring the role that human signalling molecules play for the survival of Plasmodium falciparum and Plasmodium knowlesi in erythrocytes.

Our unpublished data demonstrate that infection with Plasmodium activates several human signalling pathways, including those involving the protein kinases c-MET, PAK and MEK. We have demonstrated that P. falciparum relies on the activity of these human kinases for its intra-erythrocytic survival, and that PAK is the activator of MEK1 when stimulated by parasite invasion. The parasite kinome does not include homologues of any of these kinases.

There are currently several different cancer chemotherapy drugs in the development pipeline that target MEK1. Trametinib was the first MEK1 inhibitor to be approved for treatment (of melanoma) by the FDA in January 2014.

Here, we present data showing that trametinib - a highly selective allosteric MEK1 inhibitor - kills blood stage Plasmodium falciparum and Plasmodium knowlesi with low nanomolar IC50s in vitro. We are currently using this as a tool to explore the role of MEK1 pathways in the parasite using metabolomics and IR spectroscopy. Overall, this work paves the way for the repurposing of anticancer drugs for the treatment of malaria.