Abstract 1740: Analogs of OSI-930 as potent ABCG2-mediated multidrug resistance reversal agents

Abstract

Abstract OSI-930 {N-(4-trifluoromethoxyphenyl) 3-((quinolin-4-ylmethyl) amino) thiophene-2-carboxamide}, a dual c-Kit and KDR tyrosine kinase inhibitor, has been reported to be undergoing Phase I dose escalation study in cancer patients. A series of sixteen pyridyl and phenyl analogs (JP compounds) of OSI-930 was designed and synthesized. Extensive screening of these compounds led to the discovery that nitropyridyl and nitrophenyl analogs of OSI-930, JP1 and JP3, were effective in reversing ABC subfamily G member 2 (ABCG2/BCRP/MXR) transporter-mediated multidrug resistance (MDR). In the present study, JP1 and JP3 significantly sensitized ABCG2-expressing cells to established substrates of ABCG2 including mitoxantrone, SN-38 and doxorubicin in a concentration-dependent manner, but not to the non-ABCG2 substrate cisplatin. Furthermore, JP1 and JP3 were unable to reverse ABCB1- or ABCC1-mediated MDR indicating their selectivity for ABCG2. Western blot analysis was used to evaluate ABCG2 expression and it was found that neither JP1 nor JP3 significantly altered ABCG2 protein expression during the course of our experiment. Accumulation study with an ABCG2 substrate [3H]-mitoxantrone demonstrated that JP1 and JP3 increased the intracellular accumulation of [3H]-mitoxantrone. JP1 and JP3 also significantly inhibited the transport of [3H]-methotrexate by ABCG2 in the in vitro transport assays using membrane vesicles. Importantly, both JP1 and JP3 efficaciously stimulated the activity of ATPase of ABCG2 and inhibited the photoaffinity labeling of this transporter with its substrate [125I]-iodoarylazidoprazosin. Results from the present study suggest that analogs of OSI-930, JP1 and JP3, specifically inhibit the function of ABCG2 through direct interaction with its substrate binding site(s). Thus the OSI-930 analogs represent a new class of potential reversal compounds for the treatment of MDR in ABCG2 over-expressing tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1740. doi:10.1158/1538-7445.AM2011-1740