The Supplementary Material contains additional characterization for the compounds mentioned in the paper. We have provided melting point, 1H NMR and low resolution mass spectrometry data as well as HPLC purity for these known compounds. We have also provided a general synthetic method for the 9-amino acridine derivatives and detailed synthetic details and full characterization, including elemental analysis, for the new compound 10 (3,6-DMAD).
ARTICLE 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 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 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, 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.
