Novel Anticancer Drug Restores Tumor Cell Apoptotic Pathways

Cancer researchers have developed a drug that blocks a prosurvival gene in cancer cells and renders them vulnerable to elimination from the body by classical cell death (apoptotic) pathways.

The prosurvival protein BCL-XL is often overexpressed in solid tumors and it renders malignant tumor cells resistant to anticancer therapeutics. BCL-XL (B-cell lymphoma-extra-large) is a transmembrane molecule in the mitochondria. It is a member of the BCL-2 family of proteins, and acts as a prosurvival protein by preventing the release of mitochondrial contents such as cytochrome c, which would lead to caspase activation. BCL-2 (B-cell lymphoma 2) was the founding member of the BCL-2 family of apoptosis regulator proteins encoded by the gene of the same name. The formal name for BCL-2 is B-cell lymphoma 2, as it was the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in follicular lymphomas.


Investigators at the Walter and Eliza Hall Institute (Victoria, Australia) and their colleagues at the biotech company Genentech (San Francisco, CA, USA) sought to develop a drug that would inhibit specifically BCL-XL without affecting other BCL-2 family proteins.

To this end, they employed a high-throughput screen to discover a new series of small molecules targeting BCL-XL and then used this structure to guide development of the drug by medicinal chemistry. They reported in the April 21, 2013, online edition of the journal Nature Chemical Biology that the optimized compound, WEHI-539, had high affinity (subnanomolar range) and selectivity for BCL-XL and potently killed cells by selectively antagonizing its prosurvival activity. WEHI-539 was found to belong to the class of anti-cancer drugs called "BH3-mimetics.” Other drugs in this class include navitoclax (ABT-263) and ABT-199/GDC-0199, which are currently in clinical trials for the treatment leukemia and lymphoma.

Senior author Dr. Guillaume Lessene, professor of chemical biology at the Walter and Eliza Hall Institute, said, "That the development of WEHI-539 was an important milestone on the way to creating potential anticancer 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."

"We were very excited to see the team's work culminate in a compound that specifically inhibits BCL-XL," said Dr. Lessene. "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."

Related Links:
Walter and Eliza Hall Institute
Genentech