Abstract 4419: Design, synthesis and biological evaluation of N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide analog as a promising inhibitor of the multidrug resistance-linked ABCG2 transporter

Abstract

Abstract Abstract: Despite the current advances in cancer drug discovery, cancer cells often develop resistance to chemotherapeutic agents leading to poor clinical outcomes. The phenomenon of multidrug resistance (MDR) is prevalent among tumor populations; wherein cancer cells are rendered resistant to structurally and mechanistically unrelated drugs. Of the several factors responsible for the development of MDR, the overexpression of ATP-binding cassette (ABC) efflux transporters poses a serious threat towards attaining a successful chemotherapeutic outcome. The second member of the G sub-family of ABC transporters (ABCG2) is one such efflux transporter that renders the cancer cells resistant to several chemotherapeutic drugs, in turn limiting their intracellular accumulation. The blockade of this efflux pump offers a strategic approach towards increasing the efficiency of chemotherapy. Here we demonstrate the biological activity of a novel N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide analog, CCTA-1650 that blocks the efflux function of ABCG2 in vitro and in vivo in a preclinical tumor xenograft nude mouse model. Cell cytotoxicity assays performed by combining the chemotherapeutic agents with CCTA-1650 at concentrations of up to 5 μM significantly increased the sensitivity of resistant cancer cells overexpressing both the wild-type and mutant variants of ABCG2. CCTA-1650 inhibits the function of the transporter by decreasing the efflux of substrate chemotherapeutic agents as evident from accumulation and efflux studies with [3H]-mitoxantrone. Furthermore CCTA-1650 at concentrations of up to 5 μM did not affect the expression of ABCG2 transporter upon treatment with CCTA-1650. In addition, CCTA-1650 increased the ATPase activity of ABCG2 in a concentration-dependent manner. CCTA-1650 also displayed inhibition of function of the ABCG2 transporter in an in vivo tumor xenograft nude mouse model. CCTA-1650 at a dose of 30 mg/kg significantly sensitized the resistant tumors to doxorubicin. This effect obtained with combining chemotherapeutic agents with an inhibitor of ABCG2 function both in vitro and in vivo demonstrates the usefulness of CCTA-1650 for the treatment of drug-resistant tumors in the clinic. Citation Format: Atish S. Patel, Tianwen Li, Nagaraju Anreddy, Yufen Zhao, Rishil J. Kathawala, Yijun Wang, Suresh V. Ambudkar, Zhe-Sheng Chen, Changmei Cheng. Design, synthesis and biological evaluation of N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide analog as a promising inhibitor of the multidrug resistance-linked ABCG2 transporter. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4419. doi:10.1158/1538-7445.AM2015-4419