Researchers have designed a new class of chemical compound that selectively inhibits an important cancer protein called Aurora-A kinase. The discovery will allow scientists to study the protein in more detail, potentially leading to the development of new cancer treatments.
Scientists from The Institute of Cancer Research, London, used crystallography to analyse the structure of Aurora-A kinase then employed computer modelling to design chemicals that would attach to specific sites on the protein. They created chemicals, called Imidazo[4,5‑b]pyridine derivatives, and showed they attached to Aurora-A kinase without also binding to similar proteins.
Aurora-A kinase is one of a set of three similar molecules – the others are Aurora-B and -C – which are involved in cell division, a process that cancer cells hijack to make more copies of themselves.
Researchers showed that the new inhibitors acted selectively on Aurora-A, and not Aurora-B or –C. This is an important step forwards because inhibitors previously available to researchers block the action of all three forms of Aurora kinase, hampering efforts to understand their individual roles.
Several types of cancer cells, including a large proportion of invasive breast cancer cells, have higher than normal levels of Aurora-A. Its levels are regulated partly by the master tumour suppressor protein p53, and it’s also involved in the control of another key cancer gene, MYCN. Recent studies have shown that blocking Aurora-A kinase with new drugs could tackle cancers such as neuroblastoma, a childhood cancer.
The new molecules will help researchers unpick the precise role of Aurora-A, which could help lead to new drugs that target it specifically. Some drugs which target all three Aurora proteins are currently being tested in human trials, but drugs targeted more precisely to Aurora-A could be more effective in the longer term as cancer treatments.
Study leader Professor Julian Blagg, Professor of Medicinal Chemistry at the ICR, said: “Over the last decade there has been a lot of excitement around Aurora kinase inhibitors as potential treatments for cancer. Current inhibitors work on all three types of Aurora kinase and, although we think targeting one of the types might prove more effective, we haven’t had the tools to investigate Aurora-A properly on its own.
“The discovery of these inhibitors will allow us to study Aurora-A in more detail, and potentially design more carefully targeted drugs with a greater chance of success against cancer.”
Researchers from the Division of Cancer Therapeutics at the ICR are looking in unprecedented detail at some of the proteins involved in cancer. Better understanding of their shape helps chemists to design targeted drugs, increasing the chance that they will show a clear benefit in clinical trials. Another recent ICR project increased our understanding of how Aurora-A is activated in cells.