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Mol Cancer Ther. 2016 Sep;15(9):2055-65. doi: 10.1158/1535-7163.MCT-15-1023. Epub 2016 Jun 15.

Acridine Derivatives as Inhibitors of the IRE1α-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma.

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Department of Radiation Oncology, Stanford University, Stanford, California.
Department of Biological Sciences, University of California, San Diego, San Diego, California.
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
High-Throughput Bioscience Center, Department of Chemical and Systems Biology, Stanford University, Stanford, California.
Ayasdi Inc., Menlo Park, California.
Department of Radiation Oncology, Ohio State University, Columbus, Ohio.
Department of Radiation Oncology, Stanford University, Stanford, California.


Using a luciferase reporter-based high-throughput chemical library screen and topological data analysis, we identified N-acridine-9-yl-N',N'-dimethylpropane-1,3-diamine (DAPA) as an inhibitor of the inositol requiring kinase 1α (IRE1α)-X-box binding protein-1 (XBP1) pathway of the unfolded protein response. We designed a collection of analogues based on the structure of DAPA to explore structure-activity relationships and identified N(9)-(3-(dimethylamino)propyl)-N(3),N(3),N(6),N(6)-tetramethylacridine-3,6,9-triamine (3,6-DMAD), with 3,6-dimethylamino substitution on the chromophore, as a potent inhibitor. 3,6-DMAD inhibited both IRE1α oligomerization and in vitro endoribonuclease (RNase) activity, whereas the other analogues only blocked IRE1α oligomerization. Consistent with the inhibition of IRE1α-mediated XBP1 splicing, which is critical for multiple myeloma cell survival, these analogues were cytotoxic to multiple myeloma cell lines. Furthermore, 3,6-DMAD inhibited XBP1 splicing in vivo and the growth of multiple myeloma tumor xenografts. Our study not only confirmed the utilization of topological data analysis in drug discovery but also identified a class of compounds with a unique mechanism of action as potent IRE1α-XBP1 inhibitors in the treatment of multiple myeloma. Mol Cancer Ther; 15(9); 2055-65.

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