YHO-13351 (free base) is the water-soluble prodrug of YHO-13177, which is a potent and specific inhibitor of BCRP.IC50 value:Target: BCRP inhibitorin vitro: YHO-13177 potentiates the cytotoxicity of SN-38, mitoxantrone, and topotecan in both BCRP-transduced human colon cancer HCT116 (HCT116/BCRP) cells and SN-38-resistant human lung cancer A549 (A549/SN4) cells that express BCRP, but had little effect in the parental cells. In addition, YHO-13177 potentiates the cytotoxicity of SN-38 in human lung cancer NCI-H460 and NCI-H23, myeloma RPMI-8226, and pancreatic cancer AsPC-1 cells that intrinsically expressed BCRP. YHO-13177 increases the intracellular accumulation of Hoechst 33342, a substrate of BCRP, at 30 minutes and partially suppresses the expression of BCRP protein at more than 24 hours after its treatment in both HCT116/BCRP and A549/SN4 cells [1].in vivo: In mice, YHO-13351 is rapidly converted into YHO-13177 after its oral or intravenous administration. Coadministration of irinotecan with YHO-13351 significantly increases the survival time of mice inoculated with BCRP-transduced murine leukemia P388 cells and suppressed the tumor growth in an HCT116/BCRP xenograft model, whereas irinotecan alone has little effect in these tumor models [1].
[1]. Yamazaki R, et al. Novel acrylonitrile derivatives, YHO-13177 and YHO-13351, reverse BCRP/ABCG2-mediated drug resistance in vitro and in vivo. Mol Cancer Ther. 2011 Jul;10(7):1252-63. [2]. Shishido Y, et al. ABCG2 inhibitor YHO-13351 sensitizes cancer stem/initiating-like side population cells to irinotecan. Anticancer Res. 2013 Apr;33(4):1379-86.