Thursday, February 28, 2013
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BCL2-associated X protein (BAX);
lymphoma 2 (BCL-2;
homology domain 3 (BH3)
Structural studies have
identified regions of BAK that could guide the development of
apoptosis-inducing compounds that could help treat cancer. Crystal structures
of BCL2 have guided the development of BH3-mimetic compounds that bind and
inhibit prosurvival proteins, but it was unclear how the BH3 domains bind and
activate distinct proapoptotic proteins, including BAX and BAK. In vitro,
full-length BAK protein was purified and photochemical crosslinking
identified a BH3 binding site on BAK that was structurally distinct from the
BH3 binding site of BAX. Ongoing work includes optimizing the potency and
specificity of BAX and BAK modulators.
Abbott Laboratories and Roche's
Inc. have navitoclax (ABT-263),
a pan-inhibitor of BCL2-family proteins, in Phase I/II testing for small cell
lung cancer and Phase I testing for other cancers.
At least six other companies have antagonists of BCL2-family proteins in
Phase II testing or earlier to treat various cancers.
Published online Feb. 28, 2013
Stapled BH3 peptides that
directly engage BAX, BAK and antiapoptotic BCL-2 family targets patented; licensed
Therapeutics Inc.; small molecules that directly engage BAX
patented; available for licensing
Leshchiner, E.S. et al.
Proc. Natl. Acad. Sci. USA; published online Feb. 12, 2013;
Contact: Loren D. Walensky, Dana-Farber Cancer Institute, Boston,
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