Abstract 5783: In vitro ADME properties of ARQ 621: A specific Eg5 inhibitor

Abstract

ARQ 621 is a potent and selective allosteric inhibitor of Eg5, a microtubule-based ATPase motor protein involved in cell division. Eg5 inhibition is recognized as a potential therapeutic strategy in cancer, supported by the observation that over-expression of Eg5 causes genomic instability and tumor formation in mice. ARQ 621 is currently being tested in a Phase I clinical trial in cancer patients. Prior to its entry into the clinic, the in vitro ADME properties of ARQ 621 were studied. Data from these studies showed that ARQ 621 had a t1/2 of 53 min in human liver microsomes. The t1/2 of ARQ 621 in male and female mouse, rat, dog and monkey liver microsomes was similar to that of human liver microsomes with t1/2 values of 43, 53, 56, 53, 47, 44, 36, and 32 minutes, respectively. Consistent with the microsomal stability data, in vitro metabolic studies conducted with individual human CYP P450 isoforms indicated that ARQ 621 was relatively stable with t1/2 values all greater than 27 min. IC50 values of ARQ 621 were measured for CYP 1A2, 2C9, 2D6, 3A4, 2C19, and 2C8 and determined to be >20, >20, >20, 4.1, 4.0, and 15 µM, respectively. ARQ 621 was found to modestly induce 1A2 but not 2A6 or 3A4. Data from in vitro Caco 2 studies demonstrated that ARQ 621 has poor GI absorption potential with a Papp value of 0.69 × 10−6 cm/s. Additionally, Caco 2 bi-directional experiments suggested that ARQ 621 may be a P-glycoprotein substrate with an efflux ratio of 45. These data are consistent with rat in vivo oral bioavailability studies in which the bioavailability of ARQ 621 was determined to be approximately 9%. Hence, ARQ 621 was subsequently developed for IV administration only. Protein binding studies conducted in human plasma showed that ARQ 621 is highly bound (∼96.4-99.2%) to plasma proteins. 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 5783.