Disabling the nuclear translocalization of RelA/NF-κB by a small molecule inhibits triple-negative breast cancer growth

Hirotaka Kanzaki, Avradip Chatterjee, Hanieh Hossein Nejad Ariani, Xinfeng Zhang, Stacey Chung, Nan Deng, V. Krishnan Ramanujan, Xiaojiang Cui, Mark I. Greene, Ramachandran Murali

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


Introduction: Constitutive activation of NF-κB has been implicated as being contributive to cancer cell growth, drug resistance, and tumor recurrence in many cancers including breast cancer. Activation of NF-κB leads to nuclear translocation of RelA, a critical component of the NF-κB transcription factor complex, which subsequently binds to specific DNA sites and activates a multitude of genes involved in diverse cell functions. Studies show that triple-negative breast cancer (TNBC) cells possess constitutively active NF-κB and concomitantly have higher levels of nuclear localization of RelA than cytoplasmic RelA. This feature is considered to be associated with the response to chemotherapy. However, currently, there is no specific inhibitor to block nuclear translocation of RelA. Methods: A structure-based approach was used to develop a small-molecule inhibitor of RelA nuclear translocation. The interaction between this molecule and RelA was verified biophysically through isothermal titration calorimetry and microscale thermophoresis. TNBC cell lines MDA-MB-231 and MDA-MB-468 and a human TNBC xenograft model were used to verify in vitro and in vivo efficacy of the small molecule, respectively. Results: We found that the small molecule, CRL1101, bound specifically to RelA as indicated by the biophysical assays. Further, CRL1101 blocked RelA nuclear translocation in breast cancer cells in vitro, and markedly reduced breast tumor growth in a triple-negative breast cancer xenograft model. Conclusion: Our study demonstrates that CRL1101 may lead to new NF-κB-targeted therapeutics for TNBC. Further, blocking of nuclear translocation of shuttling transcription factors may be a useful general strategy in cancer drug development.

Original languageEnglish
Pages (from-to)419-430
Number of pages12
JournalBreast Cancer: Targets and Therapy
Publication statusPublished - 2021
Externally publishedYes


  • Breast cancer
  • Computer aided drug design
  • Drug-target
  • Nuclear transport
  • Transcription factors

ASJC Scopus subject areas

  • Oncology


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