BibTex format
@article{Soday:2025:10.1021/acschembio.5c00112,
author = {Soday, L and Seripracharat, C and Gray, JL and Luz, AFS and Howard, RT and Singh, R and Burden, TJ and Bernardini, E and Mateus-Pinheiro, M and Petersen, J and Gunnarsson, A and Gunnarsson, J and Aagaard, A and Sjögren, T and Maslen, S and Bartlett, EJ and Iles, AF and Smith, DM and Scott, JS and Skehel, M and Davis, AM and Ressurreição, AS and Moreira, R and Rodrigues, CMP and Shenoy, AR and Tate, EW},
doi = {10.1021/acschembio.5c00112},
journal = {ACS Chemical Biology},
pages = {1527--1543},
title = {Discovery and validation of a novel class of necroptosis inhibitors targeting RIPK1},
url = {http://dx.doi.org/10.1021/acschembio.5c00112},
volume = {20},
year = {2025}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - Necroptosis is a form of programmed cell death that, when dysregulated, is associated with cancer and inflammatory and neurodegenerative diseases. Here, starting from hits identified from a phenotypic high-throughput screen for inhibitors of necroptosis, we synthesized a library of compounds containing a 7-phenylquinoline motif and validated their anti-necroptotic activity in a novel live-cell assay. Based on these data, we designed an optimized photoaffinity probe for target engagement studies and through biochemical and cell-based assays established receptor-interacting kinase 1 (RIPK1) as the cellular target, with inhibition of necroptosis arising from the prevention of RIPK1 autophosphorylation and activation. X-ray crystallography and mass spectrometry revealed that these compounds bind at the hinge region of the active conformation of RIPK1, establishing them as type I kinase inhibitors. In addition, we demonstrated in vitro synergy with type III kinase inhibitors, such as necrostatin-1 and found that lead compounds protected mice against acute inflammation in necroptosis models in vivo. Overall, we present a novel pharmacophore for inhibition of human RIPK1, a key protein involved in necroptosis, and provide a photoaffinity probe to explore RIPK1 target engagement in cells.
AU - Soday,L
AU - Seripracharat,C
AU - Gray,JL
AU - Luz,AFS
AU - Howard,RT
AU - Singh,R
AU - Burden,TJ
AU - Bernardini,E
AU - Mateus-Pinheiro,M
AU - Petersen,J
AU - Gunnarsson,A
AU - Gunnarsson,J
AU - Aagaard,A
AU - Sjögren,T
AU - Maslen,S
AU - Bartlett,EJ
AU - Iles,AF
AU - Smith,DM
AU - Scott,JS
AU - Skehel,M
AU - Davis,AM
AU - Ressurreição,AS
AU - Moreira,R
AU - Rodrigues,CMP
AU - Shenoy,AR
AU - Tate,EW
DO - 10.1021/acschembio.5c00112
EP - 1543
PY - 2025///
SN - 1554-8929
SP - 1527
TI - Discovery and validation of a novel class of necroptosis inhibitors targeting RIPK1
T2 - ACS Chemical Biology
UR - http://dx.doi.org/10.1021/acschembio.5c00112
UR - https://doi.org/10.1021/acschembio.5c00112
VL - 20
ER -