Stapling proteins in the RELA complex inhibits TNFα-induced nuclear translocation of RELA

Smit Kour; Sandeep Rana; Smitha Kizhake; Dragana Lagundžin; David Klinkebiel; Jayapal Reddy Mallareddy; Tom Huxford; Nicholas T. Woods; Amarnath Natarajan

doi:10.1039/D1CB00183C

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Stapling proteins in the RELA complex inhibits TNFα-induced nuclear translocation of RELA†

Smit Kour,‡^a Sandeep Rana,‡§^a Smitha Kizhake,^a Dragana Lagundžin,^ab David Klinkebiel,^c Jayapal Reddy Mallareddy,^a Tom Huxford,

^d Nicholas T. Woods^ae and Amarnath Natarajan

*^aef

Author affiliations

* Corresponding authors

^a Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
E-mail: anatarajan@unmc.edu

^b Mass Spectrometry and Proteomics Core Facility, University of Nebraska Medical Center, Omaha, NE 68198, USA

^c Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA

^d Structural Biochemistry Laboratory, Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA 92182, USA

^e Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA

^f Department of Pharmaceutical Sciences and Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA

Abstract

Tumor necrosis factor (TNF) α-induced nuclear translocation of the NF-κB subunit RELA has been implicated in several pathological conditions. Here we report the discovery of a spirocyclic dimer (SpiD7) that covalently modifies RELA to inhibit TNFα-induced nuclear translocation. This is a previously unexplored strategy to inhibit TNFα-induced NF-κB activation.

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DOI: https://doi.org/10.1039/D1CB00183C
Article type: Communication
Submitted: 17 Sep 2021
Accepted: 09 Oct 2021
First published: 28 Oct 2021
This article is Open Access

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RSC Chem. Biol., 2022,3, 32-36

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Stapling proteins in the RELA complex inhibits TNFα-induced nuclear translocation of RELA

S. Kour, S. Rana, S. Kizhake, D. Lagundžin, D. Klinkebiel, J. R. Mallareddy, T. Huxford, N. T. Woods and A. Natarajan, RSC Chem. Biol., 2022, 3, 32 DOI: 10.1039/D1CB00183C

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RSC Chemical Biology

Stapling proteins in the RELA complex inhibits TNFα-induced nuclear translocation of RELA†

Abstract

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Stapling proteins in the RELA complex inhibits TNFα-induced nuclear translocation of RELA

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