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BCL2-associated X protein (BAX); BCL2-antagonist/killer 1 (BAK1; BAK); B cell lymphoma 2
(BCL-2; BCL2); BCL3 homology domain 3 (BH3)

Structural studies have identified regions of BAX and BAK that could guide the development of a new class of BH3-mimetic drugs that directly trigger apoptosis and help treat cancer. Crystal structures of BCL2 have guided the development of BH3-mimetic compounds that bind and inhibit prosurvival proteins; however, it was unclear how BH3 domains bind and activate proapoptotic proteins, such as BAX and BAK. In vitro and crystallographic studies of BAX in complex with BH3 peptides have now identified domains on the protein's surface necessary for BH3-driven oligomerization and activation that triggers apoptosis. Next steps could include developing BH3-mimetic compounds that directly bind BAX and trigger or block apoptosis.
Abbott Laboratories and Roche's Genentech Inc. have navitoclax (ABT-263), a pan-inhibitor of BCL2-family proteins, in Phase I/II testing in small cell lung cancer and Phase I testing in additional cancers.
At least six additional companies have antagonists of BCL2 family proteins in development stages from preclinical to Phase II testing for cancer.

SciBX 6(6); doi:10.1038/scibx.2013.133
Published online Feb. 14, 2013

Patent status undisclosed; available for licensing

Czabotar, P.E. et al. Cell; published online Jan. 31, 2013;
Contact: Peter M. Colman, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
Contact: Peter E. Czabotar, same affiliation as above