NEWS OF THE WEEK CHEMICAL
BIOLOGY
ANALYZING PROTEIN INTERACTIONS Technique probes inhibitor-enzyme interactions comprehensively
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LOSELY RELATED ENZYMES
often serve différent cellular functions, but sorting out their distinct roles and the selectivity oftheir interactions with druglike compounds remains challenging. A new technique could accelerate basic research and drug discovery by probing sets of compound-protein interactions all at once, rather than in a tedious one-by-one manner. Professor of cellular and molecular pharmacology Kevan M. Shokat and assistant professor of neurology William A. Weiss of the University of California, San Francisco, and coworkers devised the approach and used it on phosphoinositide 3-kinases (PI3-Ks) to elucidate insulin signaling and identify a promising brain-tumor inhibitor (Cell 2006,125,733 and Cancer Celt 2006,9,341). The work "is remarkable in that it takes a fully fledged chemical genomics approach to the pharmacological targeting" ofan enzyme family, comments Giulio Superti-Furga, director ofthe Center ofMolecular Medicine at the Austrian Academy of Sciences, Vienna, on the Faculty of 1000 scientific review website. "The experimental cycle goes from the identification of new chemical entities that target the PI3-K family, to the structural basis for specificity among family members, to the use of selective compounds to assess biological function." The work "sets new standards in the use of chemistry to probe function of classes of targets, is a far cry from the majority of rather anecdotal findings on the subject, and exemplifies the power of an integrated mterdisciplinary approach to compound selectivity." Shokat, Weiss, and coworkers WWW.CEN-0NLINE.ORG
screened 55 kinases, including the entire PI3-K family, with a panel of 11 potent inhibitors and mapped
cell and animal studies to determine the effects of specific interactions on insulin signaling and brain-tumor growth. The insulin study revealed that PI3-K pllOa is the primary control point for insulin signaling in cells, casting doubt on earlier findings. And the tumor study revealed that a compound called PI-103 blocks brain-tumor cell proliferation by interacting with two
PI-103
ι ι \m m\ \m\ ο Enzyme targets
Interaction map
PIPELINE Steps in the new approach include screening compounds against enzymes, mapping the interactions, obtaining structures, and testing function in cells and animals.
the biochemical selectivities of each inhibitor for each target. They obtained crystal structures of representative inhibitor-enzyme combinations to understand the structure-activity relationships in volved. They then carried out live DRUG
Crystal structures Selected compounds
Mice
Cells
PI3-Ks: pllOa and mTOR. The new approach avoids the need "to piece together such in sights from dozens of disparate papers that trickle out overyears," says Shokat group postdoc Zachary A. Knight—STU BORMAN
SAFETY
Faulty Drug Kills Five People In China t least five people have died from kidney fail ure in the southern Chi nese province of Guangdong after being injected with a de fective drug. The problem drug is armillarisin A, used to treat gall bladder and gastric conditions. A pre liminary investigation by China's State Food & Drug Administra tion found that the drug's man ufacturer, the state-owned Qiqihar No. 2 Pharmaceutical Co., based in the northeast province of Heilongjiang, had used toxic diethylene glycol as an ingredi ent instead of the more expen sive propylene glycol. The company had obtained
A
the diethylene glycol from Wang Guiping, a man impersonating an approved supplier. For rea sons unknown, Qiqihar did not check the material before using it to produce 1.8 million faulty doses, SFDA says. Those who died had been pa tients at Sun Yat-Sen University Hospital in Guangzhou. At least eight other people who received the drug survived, although Hong Kong's South China Morn ing Post reports that more fatal ities may have occurred. The pharmaceutical plant, which employs 300 people, was closed, and Chinese police are reportedly holding Wang and several Qiqihar employees. Vice
Premier Wu Yi, one of China's most respected leaders, is per sonally spurring the inquiry, SFDA says. According to a foreign execu tive who is familiar with China's drug industry but asks not to be identified, most Chinese plants do not comply with the current Good Manufacturing Practic es followed in the U.S. He says SFDA has been attempting to correct the situation. But after requiring cGMP adherence sev eral years ago, the agency had to extend deadlines and water down requirements because too few plants could conform, the executive says.—JEAN-FRAN COIS TREMBLAY
C & E N / MAY 22, 2006
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