Over the past decade, mitotic kinesins have emerged as targets in cancer therapy. Among them, kinesin family member 11 (KIF11), also known as Eg5, is responsible for bipolar spindle formation and plays a crucial role during mitosis. Inhibition of Eg5 function leads to the formation of monopolar spindles, followed by mitotic arrest, and subsequent cell death in various cancer cell lines. Several cell-permeable small molecules have been reported to inhibit Eg5 function and have attracted great interest due to their potential as the next generation of antimitotic agents. Antimitotic agents often result in severe side effects due to non-specific cytotoxicity. Eg5 inhibitors have been suggested to overcome this challenge. These undesired effects could further be avoided by implementing a photopharmacology approach, which allows for control over the drug’s activity through a structural photoswitch embedded within its molecular structure. This research project focuses on the design, synthesis, and biological evaluation of photo-responsive Eg5 inhibitors, thus enabling modulation between states of active and inactive Eg5 solely through the action of light. This is achieved by incorporating azobenzene switches into the structures of known inhibitors (azo-extension approach). Our lead photoswitch based on EMD534085 demonstrates 7x increased potency upon light irradiation in cytotoxicity assays, a highly sought-after property in photoswitch development. Our photoswitch also promotes light-dependent mitotic arrest and the light-dependent formation of monopolar spindles.

Design, synthesis, and biological evaluation of photoswitchable Eg5 inhibitors

ACS Spring Meeting 2021

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