PhGalpha1 has been shown to increase the effectiveness of an unnamed chemotherapeutic drug by 50 per cent during a trial at the Memorial Sloan-Kettering Cancer Center in the US. The drug inhibits specific members of the Protein Kinase C (PKC) family.
These serine-threonine kinase proteins are important in the transduction of signals for cell growth. This makes them a suitable target for cancer, as well as other diseases. However, there are many different forms of PKC and non-selective inhibitors in development have run into problems with side-effects. In order to reduce these adverse effects, PharmaGap set out to design a more selective therapy.
"Our peptide lead drug (PhGalpah1) shows preferential selectivity to isoforms important in the cancers we're assessing, like colorectal cancer. These include PKCalpha and PKCzeta," Simon Goulet, the chief operating officer for PharmaGap, told DrugResearcher.com.
Several other companies are also developing drugs that target this class of proteins. Eli Lilly dropped its PKCalpha inhibitor programme for lung cancer following disappointing Phase III results for Affinitak - an antisense drug licensed from Isis Pharmaceuticals. However, Lilly still have a small molecule kinase inhibitor in Phase III trials for brain cancer (glioblastoma). Enzastaurin binds to and blocks the ATP-binding site of PKCbeta but is also thought to effect other protein kinase pathways.
The pharma heavyweight has also developed Arxxant (ruboxistaurin), a PKCbeta inhibitor that was being tested as a treatment for blood vessel damage caused by diabetes, which can lead to blindness. However, as reported by DrugResearcher.com in March , the programme recently suffered a setback and Eli Lilly has withdrawn its European approval application to the European Medicines Agency (EMEA).
KAI Pharmaceuticals is also developing a peptide-based selective inhibitor of PKC isoforms. Their lead compound, KAI-9803, inhibits a different PKC isoform - delta - and is in Phase I/II trials testing its ability to reduce damage caused by heart attacks. The company are also developing selective drugs for other isoforms, including beta, epsilon, gamma and theta - although it is not testing any of these as a potential cancer therapy. The inhibitors target the RACK membrane assembly, where PKC must dock from the cytoplasm in order to be active, disrupting the binding. PharmaGap's programme, which utilises proprietary computer models of various PKC isoforms, is aimed at targeting the PKC directly.
Novartis is also looking into this class of target. PKC412 is based on the natural product, staurosporine, and is currently in Phase II trials. The drug is designed to inhibit multiple targets, including several isoforms of PKC, the FLT-3 receptor tyrosine kinase, VEGFR-2, PDGFR, c-KIT and the Pgp-mediated multidrug resistance gene, MDR.
The cancer cell lines used in the trial are known to be highly resistant to drugs, requiring increasing doses of highly toxic chemotherapeutic agents during treatment. The ability of PharmaGap's PhGalpha1 to both improve the effectiveness of and patient's exposure to chemotherapy could have a major impact if the drug is approved, according to the company.
