Reigniting cell death

Scientists at the Walter and Eliza Hall Institute in Melbourne and their collaborators at Genentech have tailor made a new chemical compound that blocks a protein that is linked to poor responses to treatment in cancer patients.

The compound, WEHI-539, binds and blocks the function of the B-cell lymphoma-extra large (BCL-X_L) protein. BCL-X_L is a member of the BCL-2 family of proteins and acts as a pro-survival protein by preventing the release of the pro-apoptotic factor, cytochrome c, from mitochondria.

A critical factor in cancer growth is the development of this ability to bypass cell death. One way tumours do this is by overexpressing the BCL-X_L protein, which renders malignant tumour cells resistant to anticancer treatments.

High levels of BCL-X_L are also associated with poorer outcomes for patients with lung, stomach, colon and pancreatic cancer.

This ability to prevent cells from dying makes BCL-XL an attractive target for drug development - inhibiting BCL-X_L can restore cell death and make cancer cells responsive to treatment. 

WEHI-539 was developed from scratch using the three-dimensional structure of BCL-X_L to build and refine its design. It is not optimised for use in patients, but will be used as a tool for researchers to further understand how BCL-X_L controls cancer cell survival.

Instead of inhibiting multiple members of the prosurvival BCL-2 family, the researchers propose that selectively inhibiting BCL-X_L will minimise toxicity and thus reduce side effects in patients.

WEHI-539 belongs to a class of chemicals called ‘BH3-mimetics’, which all bind to the same region of BCL-X_L 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 leukaemia and lymphoma.

The research was recently published in Nature Chemical Biology.