Macrolides are a class of natural products known for their antibiotic properties and in the past few decades, scientists have also shown they can be important allies in the battle against cancer. A good example is Mycalolide B (MycB), a compound isolated from the marine sponge (Mycale sp.) that even at low molecular doses can suppress proliferation and motility of cancer cells, giving it promise for preventing and treating metastasis – a condition where cells from an original tumour spread to other organs.
But there’s a hitch – MycB is not easy to obtain from nature and it is equally hard to prepare de novo. This means making truncated synthetic analogues is a crucial step in developing new cancer treatments based on this compound.
Queen’s University structural biologist John Allingham has been working on macrolides like MycB for the past 20 years and his research has helped show how these compounds hamstring cell movement and division: they can rapidly collapse the actin cytoskeleton and prevent its reassembly. No other drugs used clinically act in the same way. That’s why Allingham and his colleagues, Andrew Craig and P. Andrew Evans, MCIC, believe MycB analogues could be the most direct way to suppress metastasis.
“We recently demonstrated that MycB potently inhibits cancer cell division, motility, and invasion of extracellular matrix,” says Queen’s cancer research expert Andrew Craig, who is working with Allingham to evaluate lab-based MycB analogues. “It therefore seemed to be the best candidate to use as a template for designing a new class of cancer fighting drugs.”
Craig, Allingham and Evans recently published a paper in the Journal of the American Chemical Society where they describe their concise and scalable route to synthesising MycB analogues that potently impair the migratory and invasive activities of metastatic breast and ovarian cancer cells.
“It is certainly early days, but the critical point is that we have proof-of-principle, with a lead that can be further optimized,” says Evans.
New challenges on the horizon
David Newman, retired from the Developmental Therapeutics Program at the United States’ National Cancer Institute (NCI), who did not take part in the research, believes this is “a very interesting application of synthetic chemistry designed to reduce the ‘size’ of the natural product Mycalolide B, while retaining the overall biological actions of the parent natural product.”
He adds, however, that an important challenge in developing new therapies based on natural products and their analogues is the compounds’ potential toxicity to healthy cells. During his 24 years in the NCI Natural Products Branch, he’s seen other projects based on natural product actin inhibitors abandoned for this reason.
To avoid this pitfall, the Queen’s University researchers are working to find ways to direct the MycB analogues specifically to cancer cells. “We are testing several tumour-specific delivery strategies so that we get selectivity and then we will test in animal models,” says Evans.
Metastases account for over 90 per cent of cancer-related deaths, which is why finding new therapies to stop this process is one of the main goals in cancer research. Preventing tumour cells from migrating through the body might give physicians and patients extra time to find the right treatment before cancer spreads.
While treatment is generally easier when cancer is discovered before metastasis, some patients are only diagnosed after the tumour has spread. Craig, Evans, and Allingham are confident that MycB analogues could help in those cases too by slowing down the further spread of cancer. Because MycB and its analogue also inhibit cell division and cause cell death, both primary and secondary tumours will be vulnerable to the compound’s effect.
The researchers also believe MycB analogues, if targeted correctly, should be effective against the majority of cancers, not only breast and ovarian.