High Content Screening of Diverse Compound LibrariesIdentifies Potent Modulators of Tubulin Dynamics

摘要

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, partiallyinhibiting colchicine but not vinblastine binding, suggesting thatit acts allosterically to the known colchicine-binding site. Thus,our results exemplify the use of phenotypic screening to identifynovel antimitotic compounds from diverse chemical libraries and characterizea family of biphenylacetamides (biphenabulins) that show promise forfurther development.