Eg5 targeting agents: From new anti-mitotic based inhibitor discovery to cancer therapy and resistance

Eg5, the product of Kif11 gene, also known as kinesin spindle protein, is a motor protein involved in the proper establishment of a bipolar mitotic spindle. Eg5 is one of the 45 different kinesins coded in the human genome of the kinesin motor protein superfamily. Over the last three decades Eg5 has attracted great interest as a promising new mitotic target. The identification of monastrol as specific inhibitor of the ATPase activity of the motor domain of Eg5 inhibiting the Eg5 microtubule motility in vitro and in cellulo sparked an intense interest in academia and industry to pursue the identification of novel small molecules that target Eg5 in order to be used in cancer chemotherapy based on the anti-mitotic strategy. Several Eg5 inhibitors entered clinical trials. Currently the field is faced with the problem that most of the inhibitors tested exhibited only limited efficacy. However, one Eg5 inhibitor, Arry-520 (clinical name filanesib), has demonstrated clinical efficacy in patients with multiple myeloma and is scheduled to enter phase III clinical trials. At the same time, new trends in Eg5 inhibitor research are emerging, including an increased interest in novel inhibitor binding sites and a focus on drug synergy with established antitumor agents to improve chemotherapeutic efficacy. This review presents an updated view of the structure and function of Eg5-inhibitor complexes, traces the possible development of resistance to Eg5 inhibitors and their potential therapeutic applications, and surveys the current challenges and future directions of this active field in drug discovery.