Using a molecular plaster to beat cancer
Scientists have found several ‘holes’ in a faulty p53 protein and discovered a potential new way to beat cancer by filling in these holes with molecular plasters.
The p53 gene is so important in cancer biology it has several of its own websites. Its role is to protect the DNA in our cells from cancer-causing damage. If cells are damaged, p53 causes cells to commit suicide, to stop them becoming cancerous. If p53 itself is damaged or missing, then DNA goes unrepaired, cells are left free to divide and grow, and cancer can begin. In fact, p53 function is impaired in virtually all human cancers.
Despite the well-known links between p53 and cancer, scientists have found it hard to develop treatments that target the protein and reactivate its cancer fighting abilities….until now.
Fixing faulty p53 with a molecular plaster
Worldwide Cancer Research grantholder Dr John Spencer, at Sussex University, is collaborating with world leading p53 researchers, Professor Sir Alan Fersht and Dr Andreas Joerger at the MRC Laboratory of Molecular Biology in Cambridge.
Dr Joerger explains “Many p53 gene mutations affect the stability of the resulting p53 protein. One such mutation is Y220C where one tiny part of it (an amino acid mutation called Y220C) has changed, like one single letter typo in a book. This change is found in around 100,000 new cancer cases every year.
p53 proteins containing the Y220C mutation have a ‘hole’ which makes them unable to maintain their correct structure for very long at normal body temperature. You can see this clearly in the image above. Figure a is the C220 mutant with the hole and figure b is the healthy Y220 p53 protein (Figures kindly provided by Oncogene). This Y220C mutation renders the protein incapable of remaining ‘on guard’ against DNA damage. We know that the protein works fine at temperatures below 25˚C, but this is not very helpful in people, where our body temperature is 37˚C.”
Dr Spencer continued “Together we have been making and screening (testing on a very large scale) for compounds (chemicals) which could act like a ‘molecular plaster’, filling in the hole and stabilising the ‘wobbly’ p53 proteins. If the hole can be plugged with a small drug-like molecule, then it becomes more stable. If it is stable, it hangs around in the cells longer and so can do its job – protect the DNA.
Filling in the hole
Our team previously identified a new compound which seems to do just that. As a medicinal chemist I am always thinking, OK I have a compound which looks like it might work, but does it look like an actual drug? Will it still work the same way in the body? What’s going to be the cost? If it’s too expensive it will never be possible. We also have to think about it from a business point of view, is it already out there on the market? Can we patent a new molecule and look to commercialize it?
This compound originally came from really blue-sky thinking, we wondered if we could do something as simple as develop a molecular ‘plaster’ to fix p53 in this really simple way.
The problem is, to give this drug to a person, they would need a tablet roughly the size of a frisbee which would be crazy, as the drug just isn’t potent enough.
That is why I applied to Worldwide Cancer Research for funding to work on improving the potency of the new compounds - to make them even better at their job and make the tablets a much more manageable size. For example if you had very low iron levels, you would have to eat an insane amount of red meat and green vegetables to try to get your iron levels up but now scientists have made small, concentrated iron pills you can take instead. That’s what we need to achieve. The aim is to tweak this compound and make similar ones that are 1000 times more potent – so you need to take 1000 times less and gets the size down to an aspirin, a much more realistic pill size for a person to take.”
Everyone here at Worldwide Cancer Research is fascinated by this project so we recently caught up with Dr Spencer and Dr Joerger to find out how the project is progressing and learn more about the men behind the ‘molecular plaster’.
How is the project progressing so far?
Dr Joerger explains “Eighteen months in and I don’t want to raise hopes too much because with medicinal chemistry it’s all in the test tube, but it’s very exciting- we’ve already managed to increase the activity so it is around 50 times more potent.
In early December we published exciting findings on this project in the scientific journal Structure. We visualized and analyzed the shape of the p53 cancer mutant Y220C when attached to small molecules designed to stabilize it. Amazingly, it revealed that some of these molecules fit into a subpocket (another small ‘hole’) which opens and closes rapidly. Now that we know the shape of this subpocket, we can use this information to design even more new, potent molecules for cancer therapy.”
Dr Spencer added “We are publishing more findings to share with the research community soon. As we have two sets of people working on this project there are lots of ideas and results are coming in thick and fast. The other day one of my students looked at the published literature and said “Oh, there’s this drug that’s already licensed in patients, it’s really similar in structure to the compound we are working on, let’s test it, see if it works” So we are! It might not work, but if it does, it’s already licensed, it’s already been through clinical trials and shown to be safe in patients, it’s a great start.
My old boss (Sir James Black, the Nobel prize winner and previous Worldwide Cancer Research Vice-President) used to say “the most fruitful basis for a new drug is an old drug” You take an old drug, you tweak it a bit, and suddenly it works against cancer, that’s great!
This is an approach we also endorse here at Worldwide Cancer Research, and you can read about two ‘old’ drugs that have been given new jobs in these previous blogs on Teaching an old drug new tricks and how a river blindness drug could be used to treat breast cancer.
What are you aiming to achieve at the end of this project?
They agreed “We will be happy if we have a good, potent compound. The next stage would be to start thinking about collaborating with others and testing it for safety and toxicity, to predict whether it can be safely given to humans. That will be a major step forward, with the potential to help thousands of patients every year. But that is all a way off just now.”
We certainly can’t wait to read the forthcoming publications and hope Drs Spencer and Joerger can continue improving the potency and cutting that Frisbee shaped pill down to size.
You can access the Structure paper online
Transient Protein States for the Design of Small-Molecule Stabilizers of Mutant p53. Joerger, A. C.; Bauer, M. R.; Wilcken, R.; Baud, M. G.; Harbrecht, H.; Exner, T. E.; Boeckler, F. M.; Spencer, J.; Fersht, A. R. Structure, 2015, 23, 2246-2255.