Novel non-peptide small molecules preventing IKKβ/NEMO association inhibit NF-κB activation in LPS-stimulated J774 macrophages

Biochemical Pharmacology
Francesca De FalcoAntonio Lavecchia

Abstract

Nuclear Factor-κB (NF-κB) is a transcription factor regulating several genes involved in important physiological and pathological processes. NF-κB has been found constitutively activated in many inflammatory/immune diseases. In addition, a positive correlation between persistent activation of NF-κB and tumor promotion has been demonstrated. Since the IKK (IκB kinase) activation is an indispensable component of all pro-inflammatory signaling pathways leading to NF-κB activation, considerable efforts have been done in order to develop novel anti-inflammatory therapeutics targeting IKK. Association of the IKK complex relies on critical interactions between the C-terminus NBD (NEMO binding domain) of the catalytic subunits IKKα and IKKβ, and the regulatory subunit NEMO (NF-κB Essential Modulator). Thus, this IKK/NEMO interacting region provides an attractive target to prevent the IKK complex formation and NF-κB activation. In this regard, we have identified non-peptide small molecule disruptors of IKKβ/NEMO complex through a structure-based virtual screening (SBVS) of the NCI chemical library. Phenothiazine 22 and its close analogues (22.2, 22.4 and 22.10) were able to reduce nitrite production and iNOS mRNA expression in J774 muri...Continue Reading

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Citations

May 10, 2017·Pharmaceutical Patent Analyst·Hermann Am Mucke
Nov 15, 2017·Applied Biochemistry and Biotechnology·Nivya JamesK Ramanathan
Mar 7, 2018·Applied Biochemistry and Biotechnology·Nivya James, K Ramanathan
Apr 27, 2019·Expert Opinion on Drug Discovery·Olivia Slater, Maria Kontoyianni
Aug 23, 2017·Biomedicines·Federica BegalliGuido Franzoso
Mar 1, 2019·Scientific Reports·Adam H BarczewskiMaria Pellegrini
May 10, 2017·Cell Biochemistry and Biophysics·Nivya James, K Ramanathan
Jun 19, 2018·Applied Biochemistry and Biotechnology·K RohiniK Ramanathan
Sep 18, 2020·International Journal of Molecular Sciences·Hye Jin KoYeon Soo Han
Aug 23, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Suhaib SadiqAbdul Rauf Siddiqi
Sep 4, 2018·Journal of the American Chemical Society·Curran A RhodesDehua Pei

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