Repurposing cancer drugs – a new perspective for antimalarial drug discovery?

Simona John von Freyend, Jack D Adderley, Sarah Jackson, Amy L Burns, Anja Ruether, Anna Sexton, Darren Creek, Bayden Wood, Danny Wilson, Christian Doerig

Research output: Contribution to conferencePosterOther

Abstract

There is an urgent need for new antimalarial drugs, yet drug discovery is a cost- and time-intensive process. The repurposing of approved drugs, or chemicals that have previously undergone several phases of clinical trials, would be an ideal strategy to circumvent cost and time requirements of drug discovery.
With this purpose in mind our laboratory is exploring the role human signalling molecules are playing for the survival of Plasmodium falciparum and Plasmodium knowlesi in erythrocytes.
We have exciting new data, which demonstrates that the infection with Plasmodium activates several human signalling pathways, including c-MET, Raf, PAK and MEK. We have demonstrated that Plasmodium falciparum relies for its intra-erythrocytic survival on the activity of these human kinases and have shown that PAK is the activator of MEK1 when stimulated by parasite invasion. The parasite itself lacks any structural homologues of any of these kinases.
This is extremely promising, as these human kinases play a role during the development of several cancers and are therefore prime targets for cancer drug development.
There are currently several different 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 specific 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. In addition to this we are investigating the feasibility of repurposing drugs primarily designed to treat cancers for the treatment of malaria.


Original languageEnglish
Publication statusPublished - 3 Jul 2018
EventFirst Malaria World Congress - Melbourne Convention & Exhibition Centre, Melbourne, Australia
Duration: 1 Jul 20185 Jul 2018
Conference number: 1st
https://www.malariaworldcongress.org/

Conference

ConferenceFirst Malaria World Congress
Abbreviated titleMWC
CountryAustralia
CityMelbourne
Period1/07/185/07/18
Internet address

Cite this

John von Freyend, S., Adderley, J. D., Jackson, S., Burns, A. L., Ruether, A., Sexton, A., ... Doerig, C. (2018). Repurposing cancer drugs – a new perspective for antimalarial drug discovery?. Poster session presented at First Malaria World Congress, Melbourne, Australia.
John von Freyend, Simona ; Adderley, Jack D ; Jackson, Sarah ; Burns, Amy L ; Ruether, Anja ; Sexton, Anna ; Creek, Darren ; Wood, Bayden ; Wilson, Danny ; Doerig, Christian. / Repurposing cancer drugs – a new perspective for antimalarial drug discovery?. Poster session presented at First Malaria World Congress, Melbourne, Australia.
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John von Freyend, S, Adderley, JD, Jackson, S, Burns, AL, Ruether, A, Sexton, A, Creek, D, Wood, B, Wilson, D & Doerig, C 2018, 'Repurposing cancer drugs – a new perspective for antimalarial drug discovery?' First Malaria World Congress, Melbourne, Australia, 1/07/18 - 5/07/18, .

Repurposing cancer drugs – a new perspective for antimalarial drug discovery? / John von Freyend, Simona; Adderley, Jack D; Jackson, Sarah; Burns, Amy L; Ruether, Anja; Sexton, Anna; Creek, Darren; Wood, Bayden; Wilson, Danny; Doerig, Christian.

2018. Poster session presented at First Malaria World Congress, Melbourne, Australia.

Research output: Contribution to conferencePosterOther

TY - CONF

T1 - Repurposing cancer drugs – a new perspective for antimalarial drug discovery?

AU - John von Freyend, Simona

AU - Adderley, Jack D

AU - Jackson, Sarah

AU - Burns, Amy L

AU - Ruether, Anja

AU - Sexton, Anna

AU - Creek, Darren

AU - Wood, Bayden

AU - Wilson, Danny

AU - Doerig, Christian

PY - 2018/7/3

Y1 - 2018/7/3

N2 - There is an urgent need for new antimalarial drugs, yet drug discovery is a cost- and time-intensive process. The repurposing of approved drugs, or chemicals that have previously undergone several phases of clinical trials, would be an ideal strategy to circumvent cost and time requirements of drug discovery. With this purpose in mind our laboratory is exploring the role human signalling molecules are playing for the survival of Plasmodium falciparum and Plasmodium knowlesi in erythrocytes. We have exciting new data, which demonstrates that the infection with Plasmodium activates several human signalling pathways, including c-MET, Raf, PAK and MEK. We have demonstrated that Plasmodium falciparum relies for its intra-erythrocytic survival on the activity of these human kinases and have shown that PAK is the activator of MEK1 when stimulated by parasite invasion. The parasite itself lacks any structural homologues of any of these kinases. This is extremely promising, as these human kinases play a role during the development of several cancers and are therefore prime targets for cancer drug development. There are currently several different 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 specific 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. In addition to this we are investigating the feasibility of repurposing drugs primarily designed to treat cancers for the treatment of malaria.

AB - There is an urgent need for new antimalarial drugs, yet drug discovery is a cost- and time-intensive process. The repurposing of approved drugs, or chemicals that have previously undergone several phases of clinical trials, would be an ideal strategy to circumvent cost and time requirements of drug discovery. With this purpose in mind our laboratory is exploring the role human signalling molecules are playing for the survival of Plasmodium falciparum and Plasmodium knowlesi in erythrocytes. We have exciting new data, which demonstrates that the infection with Plasmodium activates several human signalling pathways, including c-MET, Raf, PAK and MEK. We have demonstrated that Plasmodium falciparum relies for its intra-erythrocytic survival on the activity of these human kinases and have shown that PAK is the activator of MEK1 when stimulated by parasite invasion. The parasite itself lacks any structural homologues of any of these kinases. This is extremely promising, as these human kinases play a role during the development of several cancers and are therefore prime targets for cancer drug development. There are currently several different 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 specific 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. In addition to this we are investigating the feasibility of repurposing drugs primarily designed to treat cancers for the treatment of malaria.

UR - http://mwc-2018.p.asnevents.com.au/days/2018-07-03/abstract/52221

M3 - Poster

ER -

John von Freyend S, Adderley JD, Jackson S, Burns AL, Ruether A, Sexton A et al. Repurposing cancer drugs – a new perspective for antimalarial drug discovery?. 2018. Poster session presented at First Malaria World Congress, Melbourne, Australia.