Induction of apoptosis promoted by Bang52; a small molecule that downregulates Bcl-x(L).
Cancer cells evade death by over-producing specific proteins that inhibit apoptosis. One such group of proteins is the Bcl-2 family, of which Bcl-x(L) is an important member. This protein binds and inhibits BAK, another protein that promotes apoptosis. While the development of chemical inhibitors that block Bcl-x(L)-BAK association have been the focus of intense research efforts, we demonstrate in this manuscript an alternative strategy to downregulate Bcl-x(L). We have identified a small molecule (Bang52) that induces apoptosis in a lymphoblast-derived cell line by lowering levels of Bcl-x(L). Since Bang52 bears no resemblance to any chemical binder of Bcl-x(L) we believe that degradation of the protein is stimulated by a new type of pathway. These findings highlight a novel approach to the development of small molecules that promote apoptosis.
Rossi
Matteo
M
Laboratory of Cell Biology, NCI, NIH, Bethesda, MD 20892, USA.
Bang
Jeong-Kyu
JK
Mazur
Sharlyn
S
Iera
Jaclyn A
JA
Phillips
Darren C
DC
Zambetti
Gerard P
GP
Appella
Daniel H
DH
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D002469:Cell Separation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015536:Down-Regulation; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000494:pharmacology; D008956:Models, Chemical; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051020:bcl-X Protein / Q000096:biosynthesis*
D000577:Amides; D000970:Antineoplastic Agents; C542966:Bang52; D006845:Hydrocarbons, Fluorinated; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein