N-quinoline-benzenesulfonamide derivatives exert potent anti-lymphoma effect by targeting NF-κB

Matko Kalac; Michael Mangone; Alison Rinderspacher; Shi-Xian Deng; Luigi Scotto; Michael Markson; Mukesh Bansal; Andrea Califano; Donald W Landry; Owen A O'Connor

doi:10.1016/j.isci.2020.101884

N-quinoline-benzenesulfonamide derivatives exert potent anti-lymphoma effect by targeting NF-κB

iScience. 2020 Nov 30;23(12):101884. doi: 10.1016/j.isci.2020.101884. eCollection 2020 Dec 18.

Authors

Matko Kalac^{1

2

3}, Michael Mangone^{1

2}, Alison Rinderspacher^{1

4}, Shi-Xian Deng^{1

4}, Luigi Scotto^{1

2}, Michael Markson³, Mukesh Bansal^{1

5

6}, Andrea Califano^{1

6

7

8

9}, Donald W Landry^{1

4}, Owen A O'Connor^{1

2

10}

Affiliations

¹ Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
² Center for Lymphoid Malignancies, Columbia University Irving Medical Center, New York, NY, USA.
³ Department of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA.
⁴ Department of Nephrology, Columbia University Irving Medical Center, New York, NY, USA.
⁵ Psychogenics Inc., Paramus, NJ, USA.
⁶ Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.
⁷ Department of Biomedical Informatics, Columbia University, New York, NY, USA.
⁸ Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
⁹ J.P. Sulzberger Columbia Genome Center, New York, NY, USA.
¹⁰ Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, VA, USA.

Abstract

We previously identified the N-quinoline-benzenesulfonamide (NQBS) scaffold as a potent inhibitor of nuclear factor-κB (NF-κB) translocation. Now, we report the structure-activity relationship of compounds with the NQBS scaffold in models of diffuse large B-cell lymphoma (DLBCL). We identified CU-O42, CU-O47, and CU-O75 as NQBS analogs with the most potent cytotoxic activity in DLBCL lines. Their anti-lymphoma effect was mediated by NF-κB sequestration to the cytoplasm of DLBCL cells. Internal Coordinates Mechanics analysis suggested direct binding between CU-O75 and IκBα/p50/p65 which leads to the stabilization of the NF-κB trimer. A whole cellular thermal shift assay confirmed direct binding of the NQBS to IκBα, an inhibitory component of the IκBα/p50/p65 trimer. Lymphoma cell line sequencing revealed CU-O75 induced downregulation of NF-κB-dependent genes and DeMAND analysis identified IκBα as one of the top protein targets for CU-O75. CU-O42 was potent in inhibiting tumor growth in two mouse models of aggressive lymphomas.

Keywords: Cancer; Chemistry; Medical Biochemistry.

Abstract

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