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In an effort to identify novel mitotic inhibitors, we used a cell-based screening strategy that exploited the hypersensitivity of a yeast \u03b1-tubulin mutant strain to growth inhibition by antimitotic agents. The compounds identified inhibited yeast nuclear division and included one structural class of compounds shown to be fungus specific. MC-305,904 and structural analogs inhibited fungal cell mitosis and inhibited the in vitro polymerization of fungal tubulin but did not block mammalian cell microtubule function or mammalian tubulin polymerization. Extensive analysis of yeast mutations that specifically alter sensitivity to MC-305,904 structural analogs suggested that compounds in the series bind to a site on fungal \u03b2-tubulin near amino acid 198. Features of the proposed binding site explain the observed fungal tubulin specificity of the series and are consistent with structure-activity relationships among a library of related compounds.<\/jats:p>","DOI":"10.1128\/aac.47.7.2273-2282.2003","type":"journal-article","created":{"date-parts":[[2003,6,23]],"date-time":"2003-06-23T19:17:06Z","timestamp":1056395826000},"page":"2273-2282","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Molecular Basis for Fungal Selectivity of Novel Antimitotic Compounds"],"prefix":"10.1128","volume":"47","author":[{"given":"Thomas","family":"Lila","sequence":"first","affiliation":[{"name":"Essential Therapeutics, Mountain View, California 94043"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas E.","family":"Renau","sequence":"additional","affiliation":[{"name":"Essential Therapeutics, Mountain View, California 94043"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lori","family":"Wilson","sequence":"additional","affiliation":[{"name":"Essential Therapeutics, Mountain View, California 94043"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jay","family":"Philips","sequence":"additional","affiliation":[{"name":"Essential Therapeutics, Mountain View, California 94043"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georges","family":"Natsoulis","sequence":"additional","affiliation":[{"name":"Essential Therapeutics, Mountain View, California 94043"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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