| Structural highlights
Function
RIPK1_HUMAN Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex.[1] [2] [3]
Publication Abstract from PubMed
Receptor-interacting protein kinase 1 (RIPK1) plays an essential role in necroptosis, a form of inflammatory, caspase-independent, programmed cell death. Allosteric inhibitors of RIPK1 have been shown to block necroptotic cell death and thus may offer potential therapeutic opportunities across a range of infectious, autoimmune, and neurodegenerative diseases. We report the structure-informed discovery of a novel series of bridged benzoazepine amides as part of our efforts to develop a CNS-penetrant small-molecule inhibitor of RIPK1 with a low projected oral human dose.
The Discovery of Bridged Benzoazepine Amides as Selective Allosteric Modulators of RIPK1.,Chen JL, Methot JL, Mitcheltree MJ, Musacchio A, Corcoran EB, Feng G, Lammens A, Maskos K, Palte RL, Rickard MM, Otte KM, Mansueto MS, Venkat S, Sondey C, Thomsen M, Lesburg CA, Fradera X, Fell MJ, DiMauro EF, Siliphaivanh P ACS Med Chem Lett. 2025 Apr 14;16(5):811-818. doi: , 10.1021/acsmedchemlett.5c00063. eCollection 2025 May 8. PMID:40365380[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2000 Dec;1(6):489-95. PMID:11101870 doi:10.1038/82732
- ↑ Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009 Jun 12;137(6):1112-23. doi: 10.1016/j.cell.2009.05.037. PMID:19524513 doi:10.1016/j.cell.2009.05.037
- ↑ He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009 Jun 12;137(6):1100-11. doi: 10.1016/j.cell.2009.05.021. PMID:19524512 doi:10.1016/j.cell.2009.05.021
- ↑ Chen JL, Methot JL, Mitcheltree MJ, Musacchio A, Corcoran EB, Feng G, Lammens A, Maskos K, Palte RL, Rickard MM, Otte KM, Mansueto MS, Venkat S, Sondey C, Thomsen M, Lesburg CA, Fradera X, Fell MJ, DiMauro EF, Siliphaivanh P. The Discovery of Bridged Benzoazepine Amides as Selective Allosteric Modulators of RIPK1. ACS Med Chem Lett. 2025 Apr 14;16(5):811-818. PMID:40365380 doi:10.1021/acsmedchemlett.5c00063
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