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

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.

SUBMITTER: Kalac M 

PROVIDER: S-EPMC7744703 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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<i>N</i>-quinoline-benzenesulfonamide derivatives exert potent anti-lymphoma effect by targeting NF-κB.

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

iScience 20201130 12

We previously identified the <i>N</i>-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. Int  ...[more]

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