Scientists have made the surprise discovery of an exciting new way of blocking a crucial cancer protein that has proved extremely difficult to target.
Their study took one approach to targeting the molecule – but ended up revealing a second, completely new, line of attack. The discovery has the potential to lead to new cancer drugs that target the protein.
The protein – known as heat shock protein 72 or HSP72 – plays an important role in allowing cancer cells to become resistant to treatment, but traditional approaches to designing drugs to block it have so far failed.
The researchers believe they have discovered a fatal flaw in the protein which could be exploited through a new generation of cancer treatments.
Controlling how HSP72 works
Scientists at The Institute of Cancer Research, London, used a crystal structure of HSP72 to design a prototype drug, which permanently removes the protein from the cancer cell, so can overcome the challenges this protein presents.
Irreversible inhibitors, like this prototype drug, usually work by forming a permanent chemical bond with a particular type of amino acid called a cysteine. The researchers therefore modified an existing type of inhibitor called 8-N-benzyladenosines to attach to a cysteine in HSP72.
While their newly designed irreversible inhibitor was apparently successful in permanently inhibiting HSP72, unexpectedly the cysteine amino acid was not responsible.
The researchers found the inhibitor was actually binding to a different amino acid, lysine, which is important for controlling how HSP72 works.
Targeting proteins in this way is rare but could offer many unique advantages, and the scientists believe that, with further development, this approach could at last allow drugs to be created against HSP72.
Advances in medicinal chemistry
Their study, published in the prestigious international chemistry journal Angewandte Chemie, was largely funded through a PhD studentship created by Luke Johnson, Chairman of the ICR. It also received funding from Cancer Research UK.
Lead author Dr Matthew Cheeseman, Staff Scientist at the ICR, said:
“Advances in medicinal chemistry are now showing that even apparently un-druggable proteins like HSP72 can actually be effectively targeted.
“When we discovered how our inhibitor seemed to be working it was unexpected but exciting. Now that we know where the fatal flaw in HSP72 might be, we can revise the design of our inhibitor to strike it more effectively.”
Co-author Professor Keith Jones, Team Leader in Medicinal Chemistry at the ICR, said:
“We’ve been keen to find a way through the defences of HSP72, because this molecule plays an important role in cancer in helping tumours evade the effects of treatment.
“It’s exciting to have designed an inhibitor which shows such promise in blocking the activity of such an important molecule. And our study also shows that there is still room, even in the high-tech modern world of cancer research, for a serendipitous and genuinely surprising discovery.”