Acridine Derivatives as Inhibitors of the IRE1?-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma.

ABSTRACT: 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 1? (IRE1?)-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 IRE1? oligomerization and in vitro endoribonuclease (RNase) activity, whereas the other analogues only blocked IRE1? oligomerization. Consistent with the inhibition of IRE1?-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 IRE1?-XBP1 inhibitors in the treatment of multiple myeloma. Mol Cancer Ther; 15(9); 2055-65. ©2016 AACR.

SUBMITTER: Jiang D 

PROVIDER: S-EPMC5010920 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature