Features | Partner Sites | Information | LinkXpress
Sign In
JIB
GLOBETECH PUBLISHING
BioConferenceLive

Novel Anticancer Drug Restores Tumor Cell Apoptotic Pathways

By BiotechDaily International staff writers
Posted on 29 Apr 2013
Image: Dr. Guillaume Lessene (above) and his collaborators have tailor-made a new chemical compound that blocks a protein that has been linked to poor responses to treatment in cancer patients (Photo courtesy of Walter and Eliza Hall Institute, Australia).
Image: Dr. Guillaume Lessene (above) and his collaborators have tailor-made a new chemical compound that blocks a protein that has been linked to poor responses to treatment in cancer patients (Photo courtesy of Walter and Eliza Hall Institute, Australia).
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



comments powered by Disqus

Channels

Genomics/Proteomics

view channel
Image: Blocking the activity of HSP101 may imprison the malaria parasite inside its protective vacuole within the red blood cell. In the electron micrograph, the malaria parasites appear in blue and uninfected red blood cells are shown in red (Photo courtesy of the [US] National Institute of Allergy and Infectious Diseases).

Heat Shock Protein Plays Critical Role in Malaria Parasite Protein Trafficking

A pair of recent papers described the molecular operators that enable the malaria parasite Plasmodium falciparum to export a large variety of proteins across the parasitophorous vacuolar membrane (PVM)... Read more

Therapeutics

view channel
Image: This type of electronic pacemaker could become obsolete if induction of biological pacemaker cells by gene therapy proves successful (Photo courtesy of Wikimedia Commons).

Gene Therapy Induces Functional Pacemaker Cells in Pig Heart Failure Model

Cardiovascular disease researchers working with a porcine heart failure model have demonstrated the practicality of using gene therapy to replace implanted electronic pacemakers to regulate heartbeat.... Read more

Lab Technologies

view channel
Image: A one-year-old baby sits in a brain scanner, called magnetoencephalography (MEG)—a noninvasive approach to measuring brain activity. The baby listens to speech sounds such as “da” and “ta” played over headphones while researchers record her brain responses (Photo courtesy of the Institute for Learning & Brain Sciences at the University of Washington).

Brain Scanner Shows Infants’ Brains Rehearse Speech Sounds Months Before Their First Words

New research in 7- and 11-month-old infants revealed that speech sounds stimulate brain regions that coordinate and plan motor movements for speech. The new study suggests that babies’ brains begin establishing... Read more

Business

view channel

Cancer Immunotherapy Sector Predicted to Surge to USD 9 Billion Across Major Pharma Through 2022

The immunotherapy market will experience substantial growth through 2022, increasing from USD 1.1 billion in 2012 to nearly USD 9 billion in 2022 (corresponding to 23.8% annual growth) in the United Kingdom, United States, France, Germany, Italy, Spain, and Japan, according to recent market research. This notable growth... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.