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

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

RSC Chem Biol. 2021 Oct 28;3(1):32-36. doi: 10.1039/d1cb00183c. eCollection 2022 Jan 5.

Authors

Smit Kour¹, Sandeep Rana¹, Smitha Kizhake¹, Dragana Lagundžin^{1

2}, David Klinkebiel³, Jayapal Reddy Mallareddy¹, Tom Huxford⁴, Nicholas T Woods^{1

5}, Amarnath Natarajan^{1

5

6}

Affiliations

¹ Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center Omaha, NE 68198 USA anatarajan@unmc.edu.
² Mass Spectrometry and Proteomics Core Facility, University of Nebraska Medical Center Omaha, NE 68198 USA.
³ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center Omaha NE 68198 USA.
⁴ Structural Biochemistry Laboratory, Department of Chemistry & Biochemistry, San Diego State University San Diego CA 92182 USA.
⁵ Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center Omaha NE 68198 USA.
⁶ 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.