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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. ©2016 AACR.

Original publication

DOI

10.1158/1535-7163.MCT-15-1023

Type

Journal article

Journal

Mol Cancer Ther

Publication Date

09/2016

Volume

15

Pages

2055 - 2065

Keywords

Acridines, Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Survival, Cluster Analysis, Disease Models, Animal, Drug Discovery, Drug Screening Assays, Antitumor, Endoribonucleases, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, High-Throughput Screening Assays, Humans, Mice, Multiple Myeloma, Protein-Serine-Threonine Kinases, Signal Transduction, X-Box Binding Protein 1, Xenograft Model Antitumor Assays