Abstract 4429: Characterization of the kinesin spindle protein inhibitor AZD4877

Abstract

The process of mitosis is a validated point of intervention in cancer therapy and a variety of anti-mitotic drugs are successfully being used in the clinic. To date, all approved antimitotics target the spindle microtubules, thus interfering with spindle dynamics, leading to mitotic arrest and apoptosis. While effective, these drugs are also associated with a variety of side effects, including neurotoxicity. In recent years, mitotic kinesins have attracted significant attention in the search for novel, alternative mitotic drug targets. In addition, kinesin inhibitors may overcome resistance to microtubule targeting drugs.

Here we describe the pharmacological evaluation of AZD4877, a selective Eg5 inhibitor. AZD4877 exhibits potent cell growth inhibition in vitro against a broad panel of both solid and hematological tumor cell lines. Efficacy is associated with formation of monoastral spindles, mitotic block and the induction of apoptosis. AZD4877 also demonstrates activity in multiple tumor xenograft models, including primary bladder tumor explants and a Rituximab-insensitive non-Hodgkin's Lymphoma model (DoHH2T53). Combination studies with a taxane agent (Docetaxel) demonstrate additive efficacy of tumor growth inhibition, with notable tumor regrowth delay in the combination arm. In summary, AZD4877 is an active Eg5 inhibitor with potent anti-tumor activities in vitro and in vivo. The efficacy observed in combination studies and in a rituximab-resistant tumor model suggests possible clinical applications for this agent.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4429.