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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number101884
JournaliScience
Volume23
Issue number12
DOIs
StatePublished - 18 Dec 2020

Keywords

  • Cancer
  • Chemistry
  • Medical Biochemistry

Fingerprint

Dive into the research topics of 'N-quinoline-benzenesulfonamide derivatives exert potent anti-lymphoma effect by targeting NF-κB'. Together they form a unique fingerprint.

Cite this