Acridine Derivatives as Inhibitors of the IRE1α-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma

Dadi Jiang; Arvin B Tam; Muthuraman Alagappan; Michael P Hay; Aparna Gupta; Margaret M Kozak; David E Solow-Cordero; Pek Y Lum; Nicholas C Denko; Amato J Giaccia; Quynh-Thu Le; Maho Niwa; Albert C Koong

doi:10.1158/1535-7163.MCT-15-1023

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Acridine Derivatives as Inhibitors of the IRE1α-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma

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Acridine Derivatives as Inhibitors of the IRE1α-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma

Dadi Jiang, Arvin B Tam, Muthuraman Alagappan, Michael P Hay, Aparna Gupta, Margaret M Kozak, David E Solow-Cordero, Pek Y Lum, Nicholas C Denko, Amato J Giaccia, …

Molecular cancer therapeutics, Vol.15(9), pp.2055-2065

09/2016

DOI: 10.1158/1535-7163.MCT-15-1023

PMCID: PMC5010920

PMID: 27307600

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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 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.

Acridines - pharmacology

Animals

Antineoplastic Agents - pharmacology

Cell Line, Tumor

Cell Survival - drug effects

Cluster Analysis

Disease Models, Animal

Drug Discovery

Drug Screening Assays, Antitumor

Endoribonucleases - genetics

Endoribonucleases - metabolism

Gene Expression Profiling

Gene Expression Regulation, Neoplastic - drug effects

High-Throughput Screening Assays

Humans

Mice

Multiple Myeloma - genetics

Multiple Myeloma - metabolism

Protein-Serine-Threonine Kinases - genetics

Protein-Serine-Threonine Kinases - metabolism

Signal Transduction - drug effects

X-Box Binding Protein 1 - genetics

X-Box Binding Protein 1 - metabolism

Xenograft Model Antitumor Assays

Details

Title: Subtitle: Acridine Derivatives as Inhibitors of the IRE1α-XBP1 Pathway Are Cytotoxic to Human Multiple Myeloma
Creators: Dadi Jiang - Stanford University
Arvin B Tam - University of California, San Diego
Muthuraman Alagappan - Stanford University
Michael P Hay - University of Auckland, Faculty of Medical and Health Sciences
Aparna Gupta - Stanford University
Margaret M Kozak - Stanford University
David E Solow-Cordero - High Throughput Biology
Pek Y Lum - CHDI Foundation
Nicholas C Denko - The Ohio State University
Amato J Giaccia - Stanford University
Quynh-Thu Le - Stanford University
Maho Niwa - University of California, San Diego
Albert C Koong - Stanford University
Resource Type: Journal article
Publication Details: Molecular cancer therapeutics, Vol.15(9), pp.2055-2065
DOI: 10.1158/1535-7163.MCT-15-1023
PMID: 27307600
PMCID: PMC5010920
NLM abbreviation: Mol Cancer Ther
ISSN: 1535-7163
eISSN: 1538-8514
Grant note: R01 GM087415 / NIGMS NIH HHS P01 CA067166 / NCI NIH HHS P30 CA124435 / NCI NIH HHS
Language: English
Date published: 09/2016
Academic Unit: Radiation Oncology
Record Identifier: 9984313070402771

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