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receptor interacting serine/threonine kinase 3

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Target id: 2191

Nomenclature: receptor interacting serine/threonine kinase 3

Abbreviated Name: RIPK3

Family: Receptor interacting protein kinase (RIPK) family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 518 14q12 RIPK3 receptor interacting serine/threonine kinase 3
Mouse - 486 14 C3 Ripk3 receptor-interacting serine-threonine kinase 3
Rat - 478 15p13 Ripk3 receptor-interacting serine-threonine kinase 3
Previous and Unofficial Names Click here for help
RIP3 | homocysteine respondent protein HCYP2 | RIP-like protein kinase 3
Database Links Click here for help
Alphafold Q9Y572 (Hs), Q9QZL0 (Mm), Q9Z2P5 (Rn)
BRENDA 2.7.11.1
ChEMBL Target CHEMBL1795199 (Hs)
Ensembl Gene ENSG00000129465 (Hs), ENSMUSG00000022221 (Mm), ENSRNOG00000020465 (Rn)
Entrez Gene 11035 (Hs), 56532 (Mm), 246240 (Rn)
Human Protein Atlas ENSG00000129465 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:11035 (Hs), mmu:56532 (Mm), rno:246240 (Rn)
OMIM 605817 (Hs)
Pharos Q9Y572 (Hs)
RefSeq Nucleotide NM_006871 (Hs), NM_019955 (Mm), NM_139342 (Rn)
RefSeq Protein NP_006862 (Hs), NP_064339 (Mm), NP_647558 (Rn)
UniProtKB Q9Y572 (Hs), Q9QZL0 (Mm), Q9Z2P5 (Rn)
Wikipedia RIPK3 (Hs)
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SZM594 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.1 pKd 1
⤷ pKd 7.1 (Kd 7.7x10-8 M) [1]
Description: Determined in a KINOMEscan assay.
RIPK3 inhibitor 42 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.1 pKd 18
⤷ pKd 7.1 (Kd 8.1x10-8 M) [18]
TAK-632 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.0 pKd 1
⤷ pKd 7.0 (Kd 1.05x10-7 M) [1]
Description: Binding constant determined by KINOMEscan assay.
SZM679 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition <5.3 pKd 14
⤷ pKd <5.3 (Kd >5x10-6 M) [14]
RIPK1 inhibitor 22b Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.1 pKd 7
⤷ pKd 5.1 (Kd 7.2x10-6 M) [7]
ponatinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.8 pKi 10
⤷ pKi 8.8 (Ki 1.6x10-9 M) [10]
Description: Inhibition of recombinant RIPK3 in an in vitro ADP-Glo assay (Promega).
RIPK3 inhibitor 18 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 4
⤷ pIC50 8.0 (IC50 9.1x10-9 M) [4]
Immunopharmacology Comments
RIPK1 and RIPK3 are involved in necroptosis and as such are critical regulators of inflammation and cell death [11-13,15]. RIPK-targeting necroptosis inhibitors are being developed to target inflammation mediated disorders [6], including the development of novel therapeutics for the treatment of TNF-induced systemic inflammatory response syndrome (SIRS) and sepsis, as well as cancer [9,16].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:2000452 regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation ISS
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 5 GO processes
GO:0001914 regulation of T cell mediated cytotoxicity ISS
GO:0002819 regulation of adaptive immune response ISS
GO:0033077 T cell differentiation in thymus ISS
GO:0046006 regulation of activated T cell proliferation ISS
GO:0070235 regulation of activation-induced cell death of T cells ISS
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 2 GO processes
GO:0001914 regulation of T cell mediated cytotoxicity ISS
GO:0002819 regulation of adaptive immune response ISS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 6 GO processes
GO:0001914 regulation of T cell mediated cytotoxicity ISS
GO:0002819 regulation of adaptive immune response ISS
GO:0043029 T cell homeostasis ISS
GO:0046006 regulation of activated T cell proliferation ISS
GO:0070235 regulation of activation-induced cell death of T cells ISS
GO:2000452 regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation ISS
Immuno Process:  Immune system development
GO Annotations:  Associated to 4 GO processes
GO:0033077 T cell differentiation in thymus ISS
GO:0048535 lymph node development ISS
GO:0048536 spleen development ISS
GO:0048538 thymus development ISS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0032649 regulation of type II interferon production ISS
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:2000452 regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation ISS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 2 GO processes
GO:0033077 T cell differentiation in thymus ISS
GO:0046006 regulation of activated T cell proliferation ISS
Physiological Functions Click here for help
RIPK3 is an essential regulator of TNF-induced necrosis.
Species:  Mouse
Tissue: 
References:  2,5,17
Physiological Consequences of Altering Gene Expression Click here for help
RIPK3 knockout mice are devoid of inflammation inflicted tissue damage in an acute pancreatitis model, and exhibit severely impaired virus-induced tissue necrosis, inflammation, and control of viral replication.
Species:  Mouse
Tissue: 
Technique:  Gene knockout.
References:  2,5
Deletion of RIPK3 confers complete protection against lethal TNF-induced systemic inflammatory response syndrome (SIRS).
Species:  Mouse
Tissue: 
Technique:  Gene knockout.
References:  3
General Comments
The role of RIPK3 as a critical regulator of programmed necrosis (necroptosis) is reviewed in [8].

References

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1. Chen X, Zhuang C, Ren Y, Zhang H, Qin X, Hu L, Fu J, Miao Z, Chai Y, Liu ZG et al.. (2019) Identification of the Raf kinase inhibitor TAK-632 and its analogues as potent inhibitors of necroptosis by targeting RIPK1 and RIPK3. Br J Pharmacol, 176 (12): 2095-2108. [PMID:30825190]

2. Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK. (2009) Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell, 137 (6): 1112-23. [PMID:19524513]

3. Duprez L, Takahashi N, Van Hauwermeiren F, Vandendriessche B, Goossens V, Vanden Berghe T, Declercq W, Libert C, Cauwels A, Vandenabeele P. (2011) RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity, 35 (6): 908-18. [PMID:22195746]

4. Hart AC, Abell L, Guo J, Mertzman ME, Padmanabha R, Macor JE, Chaudhry C, Lu H, O'Malley K, Shaw PJ et al.. (2019) Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage. ACS Med Chem Lett, Article ASAP. DOI: 10.1021/acsmedchemlett.9b00065

5. He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X. (2009) Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell, 137 (6): 1100-11. [PMID:19524512]

6. Kopalli SR, Kang TB, Koppula S. (2016) Necroptosis inhibitors as therapeutic targets in inflammation mediated disorders - a review of the current literature and patents. Expert Opin Ther Pat, 26 (11): 1239-1256. [PMID:27568917]

7. Li Y, Xiong Y, Zhang G, Zhang L, Yang W, Yang J, Huang L, Qiao Z, Miao Z, Lin G et al.. (2018) Identification of 5-(2,3-Dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model. J Med Chem, 61 (24): 11398-11414. [PMID:30480444]

8. Moriwaki K, Chan FK. (2013) RIP3: a molecular switch for necrosis and inflammation. Genes Dev, 27 (15): 1640-9. [PMID:23913919]

9. Najafov A, Chen H, Yuan J. (2017) Necroptosis and Cancer. Trends Cancer, 3 (4): 294-301. [PMID:28451648]

10. Najjar M, Suebsuwong C, Ray SS, Thapa RJ, Maki JL, Nogusa S, Shah S, Saleh D, Gough PJ, Bertin J et al.. (2015) Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1. Cell Rep, 10 (11): 1850-60. [PMID:25801024]

11. Newton K. (2015) RIPK1 and RIPK3: critical regulators of inflammation and cell death. Trends Cell Biol, 25 (6): 347-53. [PMID:25662614]

12. Rickard JA, O'Donnell JA, Evans JM, Lalaoui N, Poh AR, Rogers T, Vince JE, Lawlor KE, Ninnis RL, Anderton H et al.. (2014) RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell, 157 (5): 1175-88. [PMID:24813849]

13. Silke J, Rickard JA, Gerlic M. (2015) The diverse role of RIP kinases in necroptosis and inflammation. Nat Immunol, 16 (7): 689-97. [PMID:26086143]

14. Sun Y, Xu L, Shao H, Quan D, Mo Z, Wang J, Zhang W, Yu J, Zhuang C, Xu K. (2022) Discovery of a Trifluoromethoxy Cyclopentanone Benzothiazole Receptor-Interacting Protein Kinase 1 Inhibitor as the Treatment for Alzheimer's Disease. J Med Chem, 65 (21): 14957-14969. [PMID:36288088]

15. Vince JE, Silke J. (2016) The intersection of cell death and inflammasome activation. Cell Mol Life Sci, 73 (11-12): 2349-67. [PMID:27066895]

16. Wang T, Jin Y, Yang W, Zhang L, Jin X, Liu X, He Y, Li X. (2017) Necroptosis in cancer: An angel or a demon?. Tumour Biol, 39 (6): 1010428317711539. [PMID:28651499]

17. Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ, Han J. (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science, 325 (5938): 332-6. [PMID:19498109]

18. Zhang H, Xu L, Qin X, Chen X, Cong H, Hu L, Chen L, Miao Z, Zhang W, Cai Z et al.. (2019) N-(7-Cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK-632) Analogues as Novel Necroptosis Inhibitors by Targeting Receptor-Interacting Protein Kinase 3 (RIPK3): Synthesis, Structure-Activity Relationships, and in Vivo Efficacy. J Med Chem, 62 (14): 6665-6681. [PMID:31095385]

How to cite this page

Receptor interacting protein kinase (RIPK) family: receptor interacting serine/threonine kinase 3. Last modified on 05/01/2023. Accessed on 26/09/2023. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2191.