Acridine Derivatives as Inhibitors of the IRE1a-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma. Molecular cancer therapeutics Jiang, D., Tam, A. B., Alagappan, M., Hay, M. P., Gupta, A., Kozak, M. M., Solow-Cordero, D. E., Lum, P. Y., Denko, N. C., Giaccia, A. J., Le, Q., Niwa, M., Koong, A. C. 2016; 15 (9): 2055-2065


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 IRE1a-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 IRE1a oligomerization and in vitro endoribonuclease (RNase) activity, while the other analogues only blocked IRE1a oligomerization. Consistent with the inhibition of IRE1a-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 IRE1a-XBP1 inhibitors in the treatment of MM.

View details for DOI 10.1158/1535-7163.MCT-15-1023

View details for PubMedID 27307600