Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB-Controlled Oxidative Stress Responses

Cancer Res. 2016 Jan 15;76(2):377-89. doi: 10.1158/0008-5472.CAN-14-2814.

Yusuke Shono ¹, Andrea Z Tuckett ¹, Hsiou-Chi Liou ², Ekaterina Doubrovina ³, Enrico Derenzini ⁴, Samedy Ouk ², Jennifer J Tsai ¹, Odette M Smith ¹, Emily R Levy ¹, Fabiana M Kreines ¹, Carly G K Ziegler ⁵, Mary I Scallion ⁴, Mikhail Doubrovin ³, Glenn Heller ⁶, Anas Younes ⁴, Richard J O'Reilly ³, Marcel R M van den Brink ⁷, Johannes L Zakrzewski ⁸

Affiliations

1 Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York.
2 ImmuneTarget Inc., San Diego, California.
3 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
4 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
5 Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Computational Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
6 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
7 Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
8 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York. ZakrzewJ@mskcc.org.

PMID: 26744524 DOI: 10.1158/0008-5472.CAN-14-2814

Abstract

NF-κB plays a variety of roles in oncogenesis and immunity that may be beneficial for therapeutic targeting, but strategies to selectively inhibit NF-κB to exert antitumor activity have been elusive. Here, we describe IT-901, a bioactive naphthalenethiobarbiturate derivative that potently inhibits the NF-κB subunit c-Rel. IT-901 suppressed graft-versus-host disease while preserving graft-versus-lymphoma activity during allogeneic transplantation. Further preclinical assessment of IT-901 for the treatment of human B-cell lymphoma revealed antitumor properties in vitro and in vivo without restriction to NF-κB-dependent lymphoma. This nondiscriminatory, antilymphoma effect was attributed to modulation of the redox homeostasis in lymphoma cells resulting in oxidative stress. Moreover, NF-κB inhibition by IT-901 resulted in reduced stimulation of the oxidative stress response gene heme oxygenase-1, and we demonstrated that NF-κB inhibition exacerbated oxidative stress induction to inhibit growth of lymphoma cells. Notably, IT-901 did not elicit increased levels of Reactive Oxygen Species in normal leukocytes, illustrating its Cancer selective properties. Taken together, our results provide mechanistic insight and preclinical proof of concept for IT-901 as a novel therapeutic agent to treat human lymphoid tumors and ameliorate graft-versus-host disease.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-124179

IT-901

≥99.0%, c-Rel Inhibitor

NF-κB

Cancer

Name
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