Small molecule binding to inhibitor of nuclear factor kappa-B kinase subunit beta in an ATP non-competitive manner

John V. Napoleon, Sarbjit Singh, Sandeep Rana, Mourad Bendjennat, Vikas Kumar, Smitha Kizhake, Nicholas Y. Palermo, Michel M. Ouellette, Tom Huxford, Amarnath Natarajan

Research output: Contribution to journalArticlepeer-review

Abstract

Inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) is a key regulator of the cannonical NF-κB pathway. IKKβ has been validated as a drug target for pathological conditions, which include chronic inflammatory diseases and cancer. Pharmacological studies revealed that chronic administration of ATP-competitive IKKβ inhibitors resulted in unexpected toxicity. We previously reported the discovery of 13-197 as a non-toxic IKKβ inhibitor that reduced tumor growth. Here, we show that 13-197 inhibits IKKβ in a ATP non-competitive manner and an allosteric pocket at the interface of the kinase and ubiquitin like domains was identified as the potential binding site.

Original languageEnglish (US)
Pages (from-to)4678-4681
Number of pages4
JournalChemical Communications
Volume57
Issue number38
DOIs
StatePublished - May 11 2021

ASJC Scopus subject areas

  • Catalysis
  • Electronic, Optical and Magnetic Materials
  • Ceramics and Composites
  • Chemistry(all)
  • Surfaces, Coatings and Films
  • Metals and Alloys
  • Materials Chemistry

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