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NEWS; OF THE WEEK DRUG DISCOVERY DETECTING DRUGS' INFLUENCE Technique reveals compounds' direct effects on protein signaling interactions A TECHNIQUE THAT DETECTS the ability ofcompounds to affect cell-signaling path- ways could aid drug research by making it easier to understand mechanisms and side effects of drug candidates. The technique, PCA (protein- fragment complementation as- say), was developed over the past decade by biochemistry professor Stephen Michnick of the Univer- sity of Montreal and coworkers as a means for predicting unknown drug activities and toxicities. Michnick, in collaboration with John K. Westwick, president and chief scientific officer of San Ra- mon, Calif-based Odyssey Thera, and coworkers have now demon- strated the technique on existing drugs (Nat. Chem. Biol, published online May 7, dx.doi.org/10.1038/ nchembio790). Odyssey Thera, cofounded by Michnick, has an exclusive license for PCA and is developing a PCA-based drug screening program. Robert T. Abraham, vice presi- dent of oncology discovery at Wy- eth, comments that PCA could improve the efficiency and prob- ability of success of drug R&D programs by making it easier to find new uses for existing agents and to screen out potentially toxic compounds at an early stage. In PCA, two proteins that are known to interact in a biochemical pathway (such as a hormone and its receptor) are modified to include fragments of a fluorescent protein and then expressed in cells. If an introduced compound causes the two proteins to interact, the frag- ments combine, fluorescence is generated, and the signal is moni- tored microscopically, showing the cellular location and timing of the induced protein interaction. Measures are taken to distinguish signals induced by introduced compoundsfromthose induced by endogenous cell components. The paper describes the use of 49 different PCA tests to screen each of 107 known drugs. Test re- sults were in line with the drugs* known structure-activity proper- ties. The study uncovered previ- ously unknown antiproliferative ac- tivitiesforfourof the drugs, includ- ing the antidepressant sertraline. Tim Mitchison, professor of systems biology at Harvard Medi- cal School, comments that PCA might not be any better than cur- rent drug assessment techniques, such as gene expression array anal- ysis, and might be more difficult to carry out. Gene expression analysis Cell-signaling receptor Fragment measures effects ofbioactive com- pounds on protein production in cells. Michnick, Westwick, and coworkers "have identified a real prob- Receptor lem and made some progress on solving it, but I doubt it's the be-all " and end-all" of drug effects analysis, Mitchison says. Michnick replies that PCA captures responses at steps of single biochemi- cal pathways, whereas gene expression changes are in- fluenced by multiple path- ways, making it difficult to attribute drug effects to specific targets. "I hope this report will inspire others to use PCA, develop other ap- proaches for direct pathway detection, and think more about how to interpret such experiments," he says.—STU BORMAN \ Activator or inhibitor 7/|\\ Drug induces protein interaction Activator or inhibitor \ Folded fluorescent protein FLUORESCENT TURN-ON In PCA, a fragment of fluorescent protein is added to each of two signaling-pathway proteins. If the signaling proteins bind to each other in the presence of a bioactive compound, proximity of the fragments enables the fluorescent protein to be reconstituted, and its fluorescence can then be monitored microscopically. RESPONSIBLE CARE Security Highlighted At Industry Gathering A merican Chemistry Council leaders say the Responsible Care program has suc- cessfully established and implement- ed clear safety and security goals for both ACC members and the U.S. chemical industry as a whole. Thus, they say, there is no need to pass legislation that mandates inherently safer manu- facturing technology. Speaking to reporters last week at the start of the annual ACC conference on the internation- al health, safety, and environmental management initiative, Fran Keeth, chair of ACC's Board Com- mittee on Responsible Care and Shell Chemical CEO, said that all ACC members have completed vulnerability assessments of their plants. Also, all 127 ACC members except one have un- dertaken the security measures required since security became a particular concern following the 2001 terrorist attacks in the U.S. Keeth did not identify the one recalcitrant member but said ACC is working with the firm to bring it into compliance. "Responsible Care is critical to our success as an advocacy organization," said Jack N. Gerard, ACC president and CEO. He bristled at the sug- gestion that Congress could pass legislation pro- posed more than a month ago by Sens. Frank R. Lautenberg (D-NJ.) and Barack Obama (D-lll.) mandating use of inherently safer technology (C&EN, April 10, page 17). He called "more serious" a bill sponsored by Sens. Susan M. Collins (R-Maine) and Joseph I. Lieberman (D-Conn.). That bill currently contains no provisions for the safer technology approach, which calls for the use of chemicals and process- es that are less likely to cause harm in the event of an accident or attack. "We've proven we are safe," Gerard said. He is not against inherently safer technology, but adds, "Why allow government to come in and set stan- dards? The industry knows better."—MARC REISCH WWW.CEN-0NLINE.ORG C&EN / MAY 15, 2006 1 1 Fragment
