Pharmacologic Inhibition of the Anaphase-Promoting Complex Induces A Spindle Checkpoint-Dependent Mitotic Arrest in the Absence of Spindle Damage

Microtubule inhibitors are important cancer drugs that induce mitotic arrest by activating the spindleassembly checkpoint (SAC), which, in turn, inhibits the ubiquitin ligase activity of the anaphase-promotingcomplex (APC). Here, we report a small molecule, tosyl-L-arginine methyl ester (TAME), which binds to theAPC and prevents its activation by Cdc20 and Cdh1. A prodrug of TAME arrests cells in metaphase withoutperturbing the spindle, but nonetheless the arrest is dependent on the SAC. Metaphase arrest inducedby a proteasome inhibitor is also SAC dependent, suggesting that APC-dependent proteolysis is requiredto inactivate the SAC. We propose that mutual antagonism between the APC and the SAC yields a positivefeedback loop that amplifies the ability of TAME to induce mitotic arrest.