Chemical approaches to understanding biological mechanisms

Conference website: http://www.faseb.org/ascb/meetings/am99/main99mtg.htm webciteHow can we identify and study factors involved in complicated biological phenomena? A few research groups have returned to a tried and true method - that of identifying specific small-molecule inhibitors and using these to study biological functions and identifying important factors in these processes. The talks in the session entitled 'Drug targets and chemical approaches to biological mechanisms' at the 39th annual meeting of the American Society for Cell Biology focused on the development of novel small molecule inhibitors of cellular processes. Most discussed the use of libraries of small molecules to identify potential lead compounds; a variety of small-molecule libraries are now available and more are being made all the time.Thomas Mayer (Harvard Medical School) identified three novel mitotic inhibitors by screening for inhibitors that increased the level of a mitotic phosphorylation event in cultured cells (indicative of a mitotic arrest) but that did not affect microtubule dynamics. One of the three causes the formation of monopolar spindles and has thus been dubbed monastrol. The target of monastrol appears to be Eg5, a tetrameric kinesin-like microtubule motor required for the maintenance and formation of the mitotic spindle. Two other inhibitors were also described, one that caused the formation of tripolar spindles and one that causes the formation of poorly organized spindles. The specificity of these effects suggests that they are interacting with single components, so the reagents should be powerful tools for further understanding the formation of the mitotic spindle. A second presentation (Sarah Vignall, University of California Berkeley) discussed the use of a library of analogs of a known inhibitor of cyclin-dependent kinases to screen for regulators of microtubule dynamics. To date, 34 compounds have been identified that affect bipolar spindle formation in vitro and c