0 131

Cited 0 times in

Identification of Pyrido[3,4-d]pyrimidine derivatives as RIPK3-Mediated necroptosis inhibitors

Authors
 Namkyoung Kim  ;  Chan-Jung Park  ;  Younghoon Kim  ;  SeongShick Ryu  ;  Hanna Cho  ;  Yunju Nam  ;  Myeonggil Han  ;  Jeon-Soo Shin  ;  Taebo Sim 
Citation
 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, Vol.259 : 115635, 2023-11 
Journal Title
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN
 0223-5234 
Issue Date
2023-11
MeSH
Apoptosis ; Humans ; Necroptosis* / drug effects ; Necrosis ; Protein Kinases* / metabolism ; Pyrimidines / chemistry ; Pyrimidines / pharmacology ; Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
Keywords
RIPK3 ; RIPK3 inhibitor ; necroptosis ; pyrido[3,4-d]pyrimidine
Abstract
Necroptosis executed by RIPK3-mediated phosphorylation of MLKL is a programmed necrotic cell death and implicated with various diseases such as sterile inflammation. We designed and synthesized pyrido[3,4-d]pyrimidine derivatives as novel necroptosis inhibitors capable of suppressing the phosphorylation of MLKL. Our SAR studies reveal that 20 possesses comparable inhibitory activity against RIPK3-mediated pMLKL in HT-29 cells relative to GSK872 (2), a representative selective RIPK3 inhibitor. Based on biochemical kinase assay results, 20 is comparable to GSK872 (2) with regard to activity against RIPK3 and less potent against RIPK1 than GSK872, indicating selectivity of 20 towards RIPK3 over RIPK1 is higher than that of GSK872. In HT-29 cells, 20 inhibits necroptosis via MLKL oligomerization impediment. Moreover, 20 suppresses migration and invasion of AsPC-1 cells by necroptosis induced- CXCL5 secretion downregulation. Significantly, 20 could relieve the TNFα-induced systemic inflammatory response syndrome in vivo. Taken together, this study would provide a useful insight into the design of novel necroptosis inhibitors possessing RIPK3-mediated pMLKL inhibitory activity. © 2023 Elsevier Masson SAS
Full Text
https://www.sciencedirect.com/science/article/pii/S0223523423006013
DOI
10.1016/j.ejmech.2023.115635
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Shin, Jeon Soo(신전수) ORCID logo https://orcid.org/0000-0002-8294-3234
Sim, Taebo(심태보)
Cho, Hanna(조한나)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/196391
사서에게 알리기
  feedback

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse

Links