Identification and Preliminary Characterization of a Novel Tasquinimod Analog that Unexpectedly Induces Mitotic Arrest by Alteration of Microtubule Dynamics.

While investigating the SAR associated with tasquinimod, whose anticancer activity is primarily derived from inhibition of S100A9 and HDAC4, we designed and prepared several analogues. We identified a potent hit (FB2) that showed cytotoxicity against several cancer cells with IC50s between 0.3 and 2.0 μM. Surprisingly, FB2 appeared to halt cells during mitosis. To better define the relevance of FB2's unanticipated action, we further explored its mechanism and found that it significantly alters microtubule dynamics. KT-1 exposed to FB2 showed an elongated cellular morphology with condensed chromosomes and mitotic spindles. FB2 also reduced the rate of microtubule regrowth in cells; however, we are unable to conclude whether this is due to direct binding to tubulin or to some indirect mechanism involving initial interaction with some other target sites. These effects on tubulin dynamics are likely responsible for defects in spindle structure, mitotic arrest, and the observed robust killing of cancer cells.