A compound that can destroy a cancer-driving protein has been developed by scientists at the Institute for Cancer Research in London. The “molecular glue”-type degrader works by sticking to a protein that drives the growth of a form of blood cancer known as B-cell lymphoma. Once the compound has latched on, the protein is tagged for destruction by cells’ natural disposal system of “protein turnover”. With further research, the team have said, the degrader could be developed into a drug to treat B-cell lymphoma.
Lymphoma is a type of blood cancer that affects the immune system — and, more specifically, white blood cells called lymphocytes.
B-cells — or B lymphocytes — are a variety that function by creating antibodies that bind to pathogens or harmful foreign substances like toxins to neutralise them. They are also capable of recruiting other cells to help destroy infected cells.
However, in B-cell lymphoma, some B lymphocytes stop working properly, and instead grow and divide out of control.
This growth is promoted by mutations in the protein BCL6, which ordinarily binds to DNA and regulates genes involved in cell division and death.
B-cell lymphoma cells need BCL6 to survive. Accordingly, finding a way to inhibit it, or reduce its levels, could provide a means to suppress the development of the blood cancer.
In their work, medicinal chemist Dr Benjamin Bellenie and his colleagues have been seeking compounds that were capable of disrupting the function of the BCL6 protein and inhibiting lymphoma cell growth in the process.
In fact, their previous study had succeeded in identifying several promising BCL6 inhibitors — some of which even had the ability to go a step further and degrade the target protein.
The problem with these compounds, however, is that while they were capable of fully depleting BCL6 in cells, they also had a low solubility in water.
This means that it is difficult to dose sufficient amounts of the compound in tests in animal models to adequately suppress BCL6 levels.
In their new study, however, the researchers report the first BCL6 molecular glue-type degrader with suitable properties to test in animal models.
They were able to identify such a compound by first working out what molecular features are needed to make the previously-identified degraders work.
Once this was established, they were then able to create a more potent compound that binds more tightly to BCL6 and has improved water solubility.
In tests in mouse models of B-cell lymphoma, the new degrader was found to have a significant, if modest, effect on BCL6 levels — with tumours growing significantly slower than in control mice who were not given the compound.
With further development, the team said — and in combination with other therapies — such BCL6-targeted molecular glue-type degraders could be used to control tumour growth.
Alongside this, the drug’s ability to deplete BCL6 in cells also has the potential to make it a very powerful tool to study BCL6-related biology.
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Dr Bellenie said: “One interesting feature of our BCL6 project was that the initial compound we discovered from our screen had low solubility, which is not an ideal feature for drugs.
“With further investigations, we realised that the component contributing to low solubility was also giving the compound its ‘glue-like’ characteristic.
“This made it very challenging to optimise the molecule as any changes to improve its solubility often resulted in loss of its ability to stick to the target effectively.
“So we’re thrilled to announce our discovery of a set of new molecular glue-type degraders for BCL6, which drives cancers including lymphoma.
“Our project was a delicate balance of optimising solubility of our candidate compounds without losing potency, and ultimately, we were able to create a compound that can bind BCL6 very tightly and form a ‘glued complex’ even at low concentrations.”
The full findings of the study were published in the Journal of Medicinal Chemistry.
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