title: High content screening of diverse compound libraries identifies potent modulators of tubulin dynamics.
abstract: Tubulin modulating agents such as the taxanes are among the most effective antimitotic cancer drugs, although resistance and toxicity present significant problems in their clinical use. However, most tubulin modulators are derived from complex natural products, which can make modification of their structure to address these problems difficult. Here, we report the discovery of new antimitotic compounds with simple structures that can be rapidly synthesized, through the phenotypic screening of a diverse compound library for the induction of mitotic arrest. We first identified a compound, which induced mitotic arrest in human cells at submicromolar concentrations. Its simple structure enabled rapid exploration of activity, defining a biphenylacetamide moiety required for activity, A family of analogues was synthesized, yielding optimized compounds that caused mitotic arrest and cell death in the low nanomolar range, comparable to clinically used antimitotic agents. These compounds can be synthesized in 1-3 steps and good yields. We show that one such compound targets tubulin, partially inhibiting colchicine but not vinblastine binding, suggesting that it acts allosterically to the known colchicine-binding site. Thus, our results exemplify the use of phenotypic screening to identify novel antimitotic compounds from diverse chemical libraries and characterize a family of biphenylacetamides (biphenabulins) that show promise for further development.
authors.affiliation: Department of Chemistry, University of Cambridge , Cambridge CB2 1EW, U.K. ; MRC Cancer Unit, University of Cambridge , Hutchison/MRC Research Centre, Biomedical Campus, Cambridge CB2 0XZ, U.K.
authors.forename: Luca
authors.initials: L
authors.lastname: Laraia
authors.affiliation: Department of Chemistry, University of Cambridge , Cambridge CB2 1EW, U.K. ; MRC Cancer Unit, University of Cambridge , Hutchison/MRC Research Centre, Biomedical Campus, Cambridge CB2 0XZ, U.K.
authors.forename: Jamie
authors.initials: J
authors.lastname: Stokes
authors.affiliation: MRC Cancer Unit, University of Cambridge , Hutchison/MRC Research Centre, Biomedical Campus, Cambridge CB2 0XZ, U.K.
authors.forename: Amy
authors.initials: A
authors.lastname: Emery
authors.affiliation: MRC Cancer Unit, University of Cambridge , Hutchison/MRC Research Centre, Biomedical Campus, Cambridge CB2 0XZ, U.K.
authors.forename: Grahame J
authors.initials: GJ
authors.lastname: McKenzie
authors.affiliation: MRC Cancer Unit, University of Cambridge , Hutchison/MRC Research Centre, Biomedical Campus, Cambridge CB2 0XZ, U.K.
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Venkitaraman
authors.affiliation: Department of Chemistry, University of Cambridge , Cambridge CB2 1EW, U.K.
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
keywords: Phenotypic screening; allosteric; antimitotics; colchicine; tubulin