NEWS OF THE WEEK
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SWITCHABLE CATALYSTS MATERIALS CHEMISTRY:
Synthetic compounds mimic enzymes’ on-off property Active (open)
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This supramolecular assembly mimics enzymes by opening in the presence of certain ions (red) to reveal its active site (blue and orange), thereby regulating polymerization of ε-caprolactone.
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PANAGIS FILIPPAKOPOULOS
off switch. But catalytically active supramolecular complexes can be designed to controllably flip back and forth between configurations that selectively mediate or inhibit a reaction, according to researchers at Northwestern University (Science 2010, 330, 66). The study suggests new strategies for designing flexible catalysts that can be regulated by simple chemical means. In response to specific chemical stimuli, such as the presence of certain ions, allosteric enzymes undergo conformational changes that can regulate enzyme activity. These conformational changes are typically triggered by binding of the ion or other chemical stimuli to a site other than the enzyme’s active site. If the same type of response could be elicited from metal-containing organic molecules, then allosterism could serve as a new type of handle with which to control the variety of reactions catalyzed by that broad class of compounds. But engineering molecules that
PERTURBING A CANCER READER CHEMICAL BIOLOGY: Blocking a protein that recognizes markers on chromatin shrinks tumors in mice
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Y TARGETING a specific protein pocket, re-
searchers have found a way to block a protein motif that reads chemical marks on genetic material that regulates the transcription of genes. The strategy could lead to new treatments for cancer and other diseases. Until recently, scientists have focused on regulating proteins that add or remove so-called epigenetic marks, such as histone deacetylase enzymes. Now, chemical biologists Jun Qi and James E. BLOCK ON (+)-JQ1 Bradner of Dana(mostly yellow) Farber Cancer interacts with a pocket Institute and on BRD4 (mostly pink) Harvard Medical through a hydrogen School, structurbond (dotted line). al biologist Stefan Knapp of Oxford WWW.CEN-ONLINE.ORG
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mimic nature in that way has remained challenging. The Northwestern team, which includes chemists Hyo Jae Yoon, Junpei Kuwabara, Jun-Hyun Kim, and Chad A. Mirkin, turned to supramolecular synthesis methods to overcome those challenges. The researchers synthesized multipart molecular assemblies that feature two large inert multi-phenylring units and a catalytically active unit containing an Al(III)-salen moiety. The multiring sections serve as blocking layers or flaps that, depending on conformation, either expose or hide the metal center, which functions as a polymerization catalyst. In a proof-of-concept demonstration, the team showed that the triple-layer assembly could mediate ring-opening polymerization of ε-caprolactone. Treating the closed and inactive form of the structure with chloride ions caused the flaps to open, thereby exposing the catalytic center and triggering polymerization. Adding a small amount of a chlorideabstracting agent caused the assembly to fold shut and terminated the polymerization. By exploiting this reversible process, the team tuned the polymers’ molecular weights. “This is a beautiful example of how the flexibility of supramolecular chemistry can be used to mimic nature,” says University of North Carolina, Chapel Hill, chemistry professor Wenbin Lin. With this approach to turning chemistry on and off, it’s easy to envision many exciting applications, he adds.—MITCH JACOBY
University and the Structural Genomics Consortium, and colleagues have found a way to block the activity of a protein module called BRD4, which neither adds nor removes but instead “reads” lysine acetylation marks on genetic material (Nature, DOI: 10.1038/nature09504). They discovered (+)-JQ1, a molecule that nestles in a largely hydrophobic pocket on BRD4, preventing the protein-protein interaction between BRD4 and acetylated histone proteins in chromatin. Giving (+)-JQ1 to mice with an aggressive and rare form of cancer in which BRD4 becomes part of an abnormal, fused protein led to tumor death. “We consider JQ1 a tool compound,” Knapp says. “It allows us to study how these readers participate in the development of disease.” Dana-Farber has filed for patents on (+)-JQ1 derivatives that might inspire drugs to treat diseases. Efforts “like this ultimately lay the foundation for clinical studies, and I think this work is an important step toward that,” says Philip A. Cole, who studies gene regulation at Johns Hopkins University School of Medicine. GlaxoSmithKline researchers led by Kevin Lee presented a similar strategy for blocking epigenetic readers in August at the ACS national meeting in Boston. “This paper shows the promise and potential of inhibition of the reader domains within epigenetics,” Lee says.—CARMEN DRAHL
OCTOBER 4, 2010
