Development of next generation anti-malarials targeting the essential parasite protein kinase PfCLK3

Despite the success of initiatives such as roll back malaria which have distributed millions of insecticide-impregnated bed nets and effective drug treatments for malaria including artemisinin combination therapies malaria still affects over 200 million people worldwide and is the cause of nearly 0.5 million deaths per annum. These figures alone might be enough to justify continued efforts to find new malaria drug treatments but more alarmingly is the fact that resistance to the current frontline treatments is now emerging which means that we are in a race to develop the next generation of drugs. This grant is designed as a pre-clinical drug discovery programme. The aim is to develop early stage drugs that can offer the potential of curing the symptoms of malaria but also importantly to prevent transmission of malaria from one person to another. The way that drugs are developed against malaria is to have the backing and support of key malaria drug discovery organisations. This includes the Bill and Melinda Gates Foundation, Medicines for Malaria Venture (MMV) and the Malaria Drug Accelerator (MalDa). It is through these organisations that drugs are ultimately developed for clinical trails. This grant is aimed at generating novel molecules that can then be used by these organisations to develop into drugs that can be tested in patients. We will do this by screening hundreds of thousands of compounds to discover molecules that inhibit our target protein called PfCLK3. We already know that molecules that inhibit the protein PfCLK3 rapidly kill the malaria parasite in a way that leads us to believe that drugs can be developed that target this protein. Once we have discovered molecules that inhibit PfCLK3 and kill the parasites we will develop these so-called hits to have properties that are necessary if they are to be effective and safe drugs. At the end of the grant we aim to have developed these hits to a sufficient extent to be fed into the MMV/Gates drug development pipeline. Such a programme is described as a hit to lead drug discovery programme and is an essential phase before further development of the lead compounds to drug candidates that can be used in trials on patients.

This programme aims to develop an Early Lead and back series of inhibitors against the malaria protein kinase PfCLK3. This protein kinase plays an essential role in RNA splicing and has been validated by us to be a target with the potential to offer prophylactic, curative and transmission blocking activity.

To deliver on this aim we have obtained the support of the malaria drug discovery community. In particular, the Medicines for Malaria Venture (MMV), Bill and Melinda Gates Foundation and the Malaria Drug Accelerator (MalDa) are making available in vitro and in vivo assay platforms what will allow this grant to test the properties of optimised PfCLK3 inhibitors against MMV's Target Candidate Profiles (TCPs) for compounds for Lead to Candidate development. The key decision makers at MMV and Gates Foundation (Jeremy Burrows and Gang Lui, respectively) have agreed to sit on our Scientific Advisory Board, which together with Javier Gamo from GSK not only means we have a strong decision making body for GO/NO GO decisions but means that MMV and Gates are kept well informed of the progress of this programme.

We will deliver on our aim through three objectives
1. Conduct hit to lead on TCMDC-135051.
Our previous studies discovered a potent and selective inhibitor to PfCLK3, namely TCMDC-135051. We plan to further develop this inhibitor in a hit to lead programme.
2. Screen for novel chemical matter and develop in a hit to lead campaign.
We have developed a high throughput assay for PfCLK3 that will be used to screen for new chemical matter at the European Lead Factory and in the Dundee Drug Discovery Unit. Hits will be optimised in a hit to lead programme
3. Test front running molecules for properties that meet MMV criteria for subsequent Lead to Candidate optimisation.
In collaboration with MMV/Gates Foundation/MalDa we will test our front-running compounds for properties that meet MMV's TCPs for further development.

Malaria drug discovery community
This programme will directly test the principle that protein kinases can be targeted in malaria. This has been a question that has not been fully addressed in the malaria field despite the fact that protein kinases essential for survival of the parasite have been identified and that there is evolutionary diversity between the parasite and human kinomes that provides a rationale for the development of parasite-selective protein kinase inhibitors. There have however been some preclinical campaigns targeting parasite kinases, for examples PfCDPK1, but these have so far not been developed into full scale drug discovery programmes. So there is a need for a programme that will inform the malaria community of the therapeutic value of targeting parasite protein kinases - this is the aim of the current programme.

Malaria splicing community
We believe that the academic malaria community interested in splicing will benefit hugely from the tools, particularly inhibitors that prevent splicing and genetically engineered parasite lines that impact on splicing. Our primary aim is to develop inhibitors to PfCLK3 for drug discovery and not to probe deeply into the molecular details of these protein kinases in RNA processing. Thus we hope that by making the tools generated in this programme freely available to experts in RNA processing and splicing will allow this community to probe how PfCLK3 is involved in spliceosome assembly and function in malaria.

Drug discovery targeting protein kinases
Protein kinases have proven to be excellent targets in human disease, particularly cancer. The big problem is however developing selective protein kinase inhibitors since the ATP binding pocket between kinases are very similar. This programme is aimed at generating selective protein kinase inhibitors and therefore will contribute to the accumulating knowledge base that is attempting to cure human disease be the design of novel highly selective protein kinase inhibitors.

Dissemination of reagents and tools
This programme will generate a good deal of novel tools including inhibitor molecules and genetically engineered parasite lines. These will be made freely available to the academic community by requests to our laboratories.