TY - JOUR
T1 - Acridine derivatives as inhibitors of the IRE1α-XBP1 pathway are cytotoxic to human multiple myeloma
AU - Jiang, Dadi
AU - Tam, Arvin B.
AU - Alagappan, Muthuraman
AU - Hay, Michael P.
AU - Gupta, Aparna
AU - Kozak, Margaret M.
AU - Solow-Cordero, David E.
AU - Lum, Pek Y.
AU - Denko, Nicholas C.
AU - Giaccia, Amato J.
AU - Le, Quynh Thu
AU - Niwa, Maho
AU - Koong, Albert C.
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/9
Y1 - 2016/9
N2 - Using a luciferase reporter-based high-throughput chemical library screen and topological data analysis, we identified Nacridine-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.
AB - Using a luciferase reporter-based high-throughput chemical library screen and topological data analysis, we identified Nacridine-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.
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U2 - 10.1158/1535-7163.MCT-15-1023
DO - 10.1158/1535-7163.MCT-15-1023
M3 - Article
C2 - 27307600
AN - SCOPUS:84990943202
SN - 1535-7163
VL - 15
SP - 2055
EP - 2065
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 9
ER -