TitleDiscovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome
AuthorsRen, Yan
Su, Yaning
Sun, Liming
He, Sudan
Meng, Lingjun
Liao, Daohong
Liu, Xiao
Ma, Yongfen
Liu, Chunyan
Li, Sisi
Ruan, Hanying
Lei, Xiaoguang
Wang, Xiaodong
Zhang, Zhiyuan
AffiliationNatl Inst Biol Sci, 7 Sci Pk Rd,Zhongguancun Life Sci Pk, Beijing 102206, Peoples R China.
Collaborat Innovat Ctr Canc Med, Beijing 100850, Peoples R China.
Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, 320 Yue Yang Rd, Shanghai 200031, Peoples R China.
Soochow Univ, Cyrus Tang Hematol Ctr, 199 Renai Rd, Suzhou 215123, Jiangsu, Peoples R China.
Peking Univ, Coll Chem & Mol Engn, Beijing, Peoples R China.
Natl Inst Biol Sci, 7 Sci Pk Rd,Zhongguancun Life Sci Pk, Beijing 102206, Peoples R China.
Zhang, ZY (reprint author), Collaborat Innovat Ctr Canc Med, Beijing 100850, Peoples R China.
KeywordsEXPERIMENTAL DISEASE-MODELS
CELL-DEATH
KINASE INHIBITORS
INDUCED SHOCK
NECROPTOSIS
NECROSIS
NECROSTATIN-1
SPECIFICITY
INJURY
ALPHA
Issue Date2017
PublisherJOURNAL OF MEDICINAL CHEMISTRY
CitationJOURNAL OF MEDICINAL CHEMISTRY.2017,60(3),972-986.
AbstractOn the basis of its essential role in driving inflammation and disease pathology, cell necrosis has gradually been verified as a promising therapeutic target for treating atherosclerosis, systemic inflammatory response syndrome (SIRS), and ischemia injury, among other diseases. Most necrosis inhibitors targeting receptor-interacting protein 1 (RIP1) still require further optimization because of weak potency or poor metabolic stability. We conducted a phenotypic screen and identified a micromolar hit with novel amide structure. Medicinal chemistry efforts yielded a highly potent, selective, and metabolically stable drug candidate, compound 56 (RIPA-56). Biochemical studies and molecular docking revealed that RIP1 is the direct target of this new series of type III kinase inhibitors. In the SIRS mice disease model, 56 efficiently reduced tumor necrosis factor alpha (TNF alpha)-induced mortality and multiorgan damage. Compared to known RIP1 inhibitors, 56 is potent in both human and murine cells, is much more stable in vivo, and is efficacious in animal model studies.
URIhttp://hdl.handle.net/20.500.11897/475190
ISSN0022-2623
DOI10.1021/acs.jmedchem.6b01196
IndexedSCI(E)
Appears in Collections:化学与分子工程学院

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