Protein farnesyl transferase inhibitors
In the late 1980s at the University of Washington in Seattle, the Gelb Laboratory together with Prof. John A. Glomset discovered that a certain type of lipid called the prenyl group was attached to specific proteins in human cells. They went on to show that both 15-carbon farnesyl and 20-carbon geranylgeranyl groups constitute the structure of these prenyl groups. Other laboratories showed that one of these farnesylated proteins is the Ras protein. Approximately 30% of all human tumours have mutations in the Ras protein that cause uncontrolled cell growth. When it became known that the Ras protein requires its farnesyl group in order to function, a large number of pharmaceutical companies began to develop inhibitors of the enzyme, protein farnesyltransferase (PFT), which acts to farnesylate the Ras protein, as potential cancer agents. Three PFT inhibitors are now being tested in anti-cancer clinical trials.
Impact of genomics
With the completion of the genome sequence of P. falciparum, it became clear that, although the malaria parasite contains PFT, it is unlikely to contain the enzyme which attaches geranylgeranyl groups to proteins. Prof. Debopam Chakrabarti was the first to show that P. falciparum contains PFT enzymatic activity. Armed with this information, a team in Seattle led by Professors Wesley C. Van Voorhis and Michael H. Gelb, began to investigate the possibility that PFT inhibitors might prove toxic to the malaria parasite. If this were found to be true, PFT could then be considered a high priority antimalarial drug target due to the possibility of capitalizing on existing medicinal chemistry and pharmacology associated with PFT inhibitors as anti-cancer agents - “piggy-backing”.
Joining forces and teaming up with MMV
Prof. Andrew Hamilton’s group at Yale University had published information on a number of potent PFT inhibitors that were being used by several academic laboratories to investigate the role of protein farnesylation in various cellular processes. Collaboration between the Seattle and Yale laboratories began, and subsequent studies soon established that blocking PFT in P. falciparum arrested the parasite’s growth. Prof. Gelb then contacted a number of pharmaceutical companies, including Schering-Plough, Bristol-Myers Squibb, Merck and Janssen Pharmaceuticals, known to have PFT inhibitors in advanced stage development as anti-cancer agents. A set of PFT inhibitors were obtained from these companies and others were synthesized in the Gelb Laboratory. Armed with the support and resources from MMV, the Washington and Yale laboratories joined forces with MMV to move forward the investigation on the potential of PFT inhibitors as new antimalarial agents.
It soon became clear that the PFT inhibitors obtained from David Floyd, Louis Lombardo and David Williams at Bristol-Myers Squibb were able to potently inhibit the P. falciparum PFT and also to block the growth of the culture (in the low nanomolar range). Biochemical studies showed that the compounds were indeed blocking protein farnesylation in the parasites. Initial studies with malaria-infected mice were encouraging as the majority of mice were cured of infection. The PFT project was named Project of the Year 2002 for its rapid progression from lead identification to optimization.
The team is currently investigating the pharmacokinetic profiles of the most promising PFT inhibitors. Many of the compounds have acceptable oral bioavailability but suffer from rapid elimination from the plasma. Detailed metabolism studies are being carried out to identify the reasons for the rapid drug clearance. It is anticipated that such information can be used to modify the lead structures in a rational way. Medicinal chemists at Yale University and at the University of Washington are also preparing new structural variants of the lead PFT inhibitors as backup compounds.
This project illustrates how the “piggyback” medicinal chemistry approach can be effective in obtaining novel antimalarials. PFT from the malaria parasite is now a well-established antimalarial drug target - one of the few new targets to emerge in the past decade.