Using a luciferase reporter-based high throughput chemical library screen and topological data analysis (TDA), we identified N-acridine-9-yl-N',N'-dimethylpropane-1,3-diamine (DAPA) as a inhibitor of the IRE1α-XBP1 pathway of the unfolded protein response (UPR). We designed a collection of analogues based on the structure of DAPA to explore structure-activity relationships (SAR) and identified N9-(3-(dimethylamino)propyl)-N3,N3,N6,N6-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, while the other analogues only blocked IRE1α oligomerization. Consistent with the inhibition of IRE1α-mediated XBP1 splicing, which is critical for multiple myeloma (MM) cell survival, these analogues were cytotoxic to MM cell lines. Furthermore, 3,6-DMAD inhibited XBP1 splicing and the growth of MM 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 MM.
- Received January 8, 2016.
- Revision received May 17, 2016.
- Accepted June 7, 2016.
- Copyright ©2016, American Association for Cancer Research.