Acridine Derivatives as Inhibitors of the IRE1α-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma.
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 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 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.
Department of Radiation Oncology, Stanford University, Stanford, California.
Dadi
D
Jiang
Department of Biological Sciences, University of California, San Diego, San Diego, California.
Arvin B
AB
Tam
Department of Radiation Oncology, Stanford University, Stanford, California.
Muthuraman
M
Alagappan
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Michael P
MP
Hay
Department of Radiation Oncology, Stanford University, Stanford, California.
Aparna
A
Gupta
Department of Radiation Oncology, Stanford University, Stanford, California.
Margaret M
MM
Kozak
High-Throughput Bioscience Center, Department of Chemical and Systems Biology, Stanford University, Stanford, California.
David E
DE
Solow-Cordero
Ayasdi Inc., Menlo Park, California.
Pek Y
PY
Lum
Department of Radiation Oncology, Ohio State University, Columbus, Ohio.
Nicholas C
NC
Denko
Department of Radiation Oncology, Stanford University, Stanford, California.
Amato J
AJ
Giaccia
Department of Radiation Oncology, Stanford University, Stanford, California.
Quynh-Thu
QT
Le
Department of Biological Sciences, University of California, San Diego, San Diego, California.
Maho
M
Niwa
Department of Radiation Oncology, Stanford University, Stanford, California. akoong@stanford.edu.
Albert C
AC
Koong
D000166:Acridines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D004195:Disease Models, Animal; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000166:Acridines; D000970:Antineoplastic Agents; D000071717:X-Box Binding Protein 1; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases