Skip to main content
 
Notice: Users may be experiencing issues with displaying some pages on stanfordhealthcare.org. We are working closely with our technical teams to resolve the issue as quickly as possible. Thank you for your patience.
Stanford Health Care

Acridine Derivatives as Inhibitors of the IRE1a-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma.

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

Abstract

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