AsianScientist (Apr. 22, 2013) – Scientists at the Walter and Eliza Hall Institute in Australia and their collaborators have tailor-made a new chemical compound that blocks a key cancer protein. The development of the compound, called WEHI-539, is an important step towards the design of a potential new anti-cancer agent.
The researchers designed the compound WEHI-539 to bind and block the function of a protein called BCL-XL that normally prevents cells from dying. BCL-XL has been linked to poor responses to treatment in cancer patients.
The death and elimination of abnormal cells in the body is an important safeguard against cancer development. But cancer cells often acquire genetic changes that allow them to escape cell death, which also reduces the effectiveness of anti-cancer treatments such as chemotherapy.
Cancer cells can become long-lived by producing high levels of BCL-XL protein, and high levels of BCL-XL are also associated with poorer outcomes for patients with lung, stomach, colon and pancreatic cancer.
Dr. Guillaume Lessene, who led the research team in collaboration with Genentech, said the development of WEHI-539 was an important milestone on the way to creating potential anti-cancer agents that act to restore cell death by inhibiting BCL-XL.
“Although WEHI-539 is not optimized for use in patients, it will be a very valuable tool for researchers to use to dissect how BCL-XL controls cancer cell survival,” he said.
WEHI-539 belongs to a class of chemicals called ‘BH3-mimetics’, which all bind to the same region of BCL-XL or related proteins. Two BH3-mimetics, called navitoclax (ABT-263) and ABT-199/GDC-0199 are currently in clinical trials for the treatment of cancer, particularly those of the blood and lymph glands (leukaemia and lymphoma).
Publishing in the journal Nature Chemical Biology, Dr. Lessene said WEHI-539 was the product of a sustained research program.
“We were very excited to see the team’s work culminate in a compound that specifically inhibits BCL-XL,” he said. “WEHI-539 is the first compound that our chemists have developed from scratch, using the three-dimensional structure of BCL-XL to build and refine its design.”
The article can be found at: Lessene et al. (2013) Structure-guided design of a selective BCL-XL inhibitor.
Source: WEHI; Photo: WEHI.
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