title: Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome.
abstract: On 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 (TNFα)-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.
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ren
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.
authors.forename: Yaning
authors.initials: Y
authors.lastname: Su
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Sun
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.
authors.forename: Sudan
authors.initials: S
authors.lastname: He
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.
authors.forename: Lingjun
authors.initials: L
authors.lastname: Meng
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.
authors.forename: Daohong
authors.initials: D
authors.lastname: Liao
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Liu
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.
authors.forename: Yongfen
authors.initials: Y
authors.lastname: Ma
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.
authors.forename: Sisi
authors.initials: S
authors.lastname: Li
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.
authors.forename: Hanying
authors.initials: H
authors.lastname: Ruan
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Lei
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: National Institute of Biological Sciences , No. 7 Science Park Road, Zhongguancun Life Science Park, Changping District, Beijing 102206, China.|Collaborative Innovation Center for Cancer Medicine , Beijing 100850, China.
authors.forename: Zhiyuan
authors.identifier: 0000-0002-2910-1986
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors*; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D013329:Structure-Activity Relationship; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy*
chemical_list: D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse