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.