Abstract
Proteins of the BCL-2 family control the mitochondrial pathway of apoptosis. Targeting these proteins proves to be an attractive strategy for anticancer therapy. The biological context is based on the fact that BH3-only members of the family are specific antagonists of prosurvival members. This prompted the identification of "BH3 mimetic" compounds. These small peptides or organic molecules indeed mimic the BH3 domain of BH3-only proteins: by selectively binding and antagonizing prosurvival proteins, they can induce apoptosis in malignant cells. Some small-molecule inhibitors of prosurvival proteins have already entered clinical trials in cancer patients and two of them have shown significant therapeutic effects. The latest developments in the field of targeting BCL-2 family proteins highlight several new antagonists of prosurvival proteins as well as direct activators of proapoptotic proteins. These compounds open up novel prospects for the development of BH3 mimetic anticancer drugs.
Highlights
Apoptosis is a cell death program intended for regulating cell number during development and tissue homeostasis as well as eliminating damaged/dangerous cells [1]
All prosurvivals can bind BAX whereas only BCLXL and MCL-1 bind to BAK. This antiapoptotic activity is antagonized by the BH3-only members: by inserting their helical BH3 region into the hydrophobic groove of the prosurvival proteins, they provoke the release of the sequestered BAX and BAK that are activated. These interactions are selective: for example NOXA binds only to MCL-1 and A1, BAD binds only to BCL-2, BCL-XL and BCL-W, whereas BIM, BID and PUMA can bind to all prosurvival proteins [1, 2]
TW-37, a rationally designed benzoylsulphonyl analog of gossypol [22, 27], was known to operate only in part as a pan-BH3 mimetic: it binds to BCL-2, BCL-XL and MCL-1 with moderate affinity, induces apoptosis depending partially on BAX/BAK activation and shows several off-target effects
Summary
Apoptosis is a cell death program intended for regulating cell number during development and tissue homeostasis as well as eliminating damaged/dangerous cells [1]. TW-37, a rationally designed benzoylsulphonyl analog of gossypol [22, 27], was known to operate only in part as a pan-BH3 mimetic: it binds to BCL-2, BCL-XL and MCL-1 with moderate affinity (sub-μM), induces apoptosis depending partially on BAX/BAK activation and shows several off-target effects. This compound binds to BCL-2 and BCL-XL with sub-nM affinity, inhibits their antiapoptotic activities and induces BAX/BAK-dependent apoptosis in small cell lung cancer cell lines.
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