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

doi:10.1039/d1cc01245b

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

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6 Scopus citations

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 language	English (US)
Pages (from-to)	4678-4681
Number of pages	4
Journal	Chemical Communications
Volume	57
Issue number	38
DOIs	https://doi.org/10.1039/d1cc01245b
State	Published - May 11 2021

ASJC Scopus subject areas

Electronic, Optical and Magnetic Materials
Catalysis
Ceramics and Composites
General Chemistry
Surfaces, Coatings and Films
Metals and Alloys
Materials Chemistry

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10.1039/d1cc01245b

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

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.",

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T1 - Small molecule binding to inhibitor of nuclear factor kappa-B kinase subunit beta in an ATP non-competitive manner

AU - Napoleon, John V.

AU - Singh, Sarbjit

AU - Rana, Sandeep

AU - Bendjennat, Mourad

AU - Kumar, Vikas

AU - Kizhake, Smitha

AU - Palermo, Nicholas Y.

AU - Ouellette, Michel M.

AU - Huxford, Tom

AU - Natarajan, Amarnath

PY - 2021/5/11

Y1 - 2021/5/11

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

Abstract

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