Scientists at Cancer Research UK's London Research Institute (LRI; now part of the Francis Crick Institute) have discovered a chemical that is highly selective in inhibiting the protein produced by a known cancer-associated gene, called atypical protein kinase C (PKC) iota.
The finding opens up a new avenue of research into anti-cancer drugs that target this protein without having a detrimental effect on closely related proteins in the same family.
Neil McDonald of LRI explained: "PKC iota is a well studied member of the PKC family that has been proposed to be an oncogene - a gene that can directly cause cancer. It can cooperate with other well-known oncogenes that are hard to stop. High levels of active PKC iota are found in many cancers and this predicts a poor clinical outcome. So our idea was that if we could prevent high levels of active PKC iota, we may reverse the disorganization and spread of cancer cells.
"The less well-studied PKC zeta has also been validated as a cancer target. The problem was how to target just PKC iota and zeta without affecting all the closely related types of PKC that have very different functions in the body and could give unpredictable side effects in patients. When we started the project, there were no credible reports of selective inhibitors against the atypical PKCs iota and zeta. The inhibitors in current research use are either 'dirty', meaning they inhibit many related proteins, or barely have any effect on inhibiting PKC iota and zeta."
He continued: "In this work we have discovered a 'clean' chemical inhibitor that is highly selective for the atypical PKCs iota and zeta. Significantly, it does not inhibit other closely related forms of PKC, which is exactly what we were after. This is important as it allows the exclusive targeting of the atypical PKCs that are known anti-cancer drug targets, without touching the diverse activities of other PKC family members."
Professor McDonald's team at LRI formed a close collaboration with the Protein Phosphorylation Laboratory and the CRT-Discovery Laboratory, all funded by Cancer Research UK. His lab purified, characterised and crystallised PKC iota bound to the selective inhibitors, while the CRT-Development Laboratory established a high-throughput assay, allowing them to test thousands of compounds very quickly, to screen for potential inhibitors. The Protein Phosphorylation Laboratory used their cell biology expertise to grow various cancer cell lines in the laboratory and test how effective the drugs were in cells.
"By teaming up these three groups, we were able to tap into a much broader base of research expertise, all working towards a shared research objective. This approach has been very successful and allowed us to move fast on this project ahead of other academic and commercial groups interested in developing PKC iota inhibitors," added Professor McDonald.
The team showed that the inhibitor not only works against purified PKC iota and zeta proteins, but also worked in the different cancer cell lines by affecting cell movement and organisation. It also reduced the viability of the cells and their ability to form colonies - which are two crucial properties for cancer cells.
The inhibitor discovered is now available as a high quality chemical tool for the entire research community, and other closely related inhibitors are being developed in partnership with a major pharmaceutical company.
Professor McDonald concluded: "Our work has important implications for cancer treatment as there are a large number of studies showing the involvement of PKC iota in a wide variety of human cancers. There is a real opportunity to use the inhibitors our study has discovered to identify even more potent compounds against PKC iota that may one day end up in the clinic."
The paper, Adenosine-binding motif mimicry and cellular effects of a thieno[2,3-d]pyrimidine-based chemical inhibitor of atypical protein kinase C isoenzymes, is published in the Biochemical Journal.
