AGENT MAKES CANCER SUICIDAL
biological SCENE
SMALL MOLECULE triggers ‘death receptor’
found on cancer cells
IN WORK that opens a new window on
The first small-molecule activators of fighting cancer while minimizing side death receptors raise hopes of overcomeffects, researchers have developed the ing such limitations. They were identifirst small molecule that interacts with a fied by a group led by Gelin Wang of the cancer-cell-surface “death receptor,” an University of Texas, Dallas, Southwestern interaction that tells cancer cells to comMedical Center and Xiaoguang Lei and mit suicide. Xiaodong Wang of the National InstiThe receptor, death receptor 5 (DR5), tute of Biological Sciences, Beijing (Nat. is rarely expressed on normal cells but is Chem. Biol., DOI: 10.1038/ present on a variety of cancer cells, so acnchembio.1153). O tivating it is likely to have few side effects The researchers NH on normal cells, although this screened a library O O of about 200,000 hypothesis remains to be O tested. compounds to find Br N Cells are proagents that induce cell S grammed to commit death in brain tumor cells. StrucHN suicide, through a process tural analysis of these agents enabled Bioymifi known as apoptosis, when the team to design a potent analog, they are exposed to sufficiently stressful which they call bioymifi. They found that conditions. Cancer cells, however, have bioymifi works by mimicking the abilmechanisms that prevent apoptosis, ity of TRAIL, the natural DR5 ligand, to helping them thrive even in the face of stimulate clustering of DR5, triggering adversity. apoptosis. For more than a decade, the drug discovGenentech Senior Staff Scientist Avi ery community has been trying to sidestep Ashkenazi, whose lab discovered TRAIL these protective mechanisms by directly and DR5, says the work by Wang, Lei, targeting components of cancer cells’ Wang, and colleagues “represents a signifimitochondrial and cell-surface (“intrinsic” cant breakthrough because it describes for and “extrinsic”) apoptosis pathways. For the first time a direct small-molecule actiexample, scientists have identified small vator of the extrinsic pathway.” molecules that inhibit the anti-apoptosis Researchers could use small-molecule protein Bcl-2, thereby activating the inactivators such as bioymifi to help investitrinsic apoptotic pathway. A few of these gate key drivers of efficacy in DR5 activamolecules are now in clinical trials for varition, he says, assuming the small-molecule ous cancers, although none has yet been agents turn out to be as free of side effects approved. as large-molecule DR5 activators have Extrinsic activators of apoptosis could proven to be. complement or exceed the capabilities of Although it is currently unclear whether intrinsic ones. But efforts to come up with the small-molecule approach “will be small-molecule activators of cancer cells’ advantageous over large-molecule strateextrinsic apoptotic pathway have been gies,” Ashkenazi adds, “it clearly has the unsuccessful. The only extrinsic activators potential to expand the pharmacological scientists have come up with are proteins tool kit that is now available to harness the that turn on four death receptors—TNFR1, extrinsic pathway for therapeutic gain.” In Fas/CD95, DR4, and DR5. But proteins that addition, he says, bioymifi’s mechanism of activate TNFR1 and Fas/CD95 cause toxicaction, stimulation of receptor clustering, ity, and those that activate DR4 and DR5 is unique and surprising and could prove disappear rapidly from the bloodstream or useful for activating other apoptosis recepare only weakly effective. tors as well.—STU BORMAN WWW.CEN-ONLINE.ORG
37
JANUARY 14, 2013
An up-to-the-minute collection of news about research and business at the interface of chemistry and biology, including coverage of biotechnology, molecular medicine, biophysics, chemical biology, neuroscience, natural products, enzymology, and structural biology.
cen.acs.org/biological
Sign up for the BIOLOGICAL SCENE NEWSLETTER— C&EN will keep you up to date with a roundup of latest news delivered to your email inbox each week.
