receptor interacting serine/threonine kinase 3 | Receptor interacting protein kinase (RIPK) family | IUPHAR/BPS Guide to PHARMACOLOGY

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receptor interacting serine/threonine kinase 3

target has curated data in GtoImmuPdb

Target id: 2191

Nomenclature: receptor interacting serine/threonine kinase 3

Abbreviated Name: RIPK3

Family: Receptor interacting protein kinase (RIPK) family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 518 14q12 RIPK3 receptor interacting serine/threonine kinase 3
Mouse - 486 14 C1 Ripk3 receptor-interacting serine-threonine kinase 3
Rat - 478 15 p13 Ripk3 receptor-interacting serine-threonine kinase 3
Previous and Unofficial Names
RIP3 | homocysteine respondent protein HCYP2 | RIP-like protein kinase 3
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SZM594 Hs Inhibition 7.1 pKd 1
pKd 7.1 (Kd 7.7x10-8 M) [1]
Description: Determined in a KINOMEscan assay.
RIPK3 inhibitor 42 Hs Inhibition 7.1 pKd 17
pKd 7.1 (Kd 8.1x10-8 M) [17]
TAK-632 Hs Inhibition 7.0 pKd 1
pKd 7.0 (Kd 1.05x10-7 M) [1]
Description: Binding constant determined by KINOMEscan assay.
RIPK1 inhibitor 22b Hs Inhibition 5.1 pKd 7
pKd 5.1 (Kd 7.2x10-6 M) [7]
ponatinib 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 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 [11-14]. 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 [9,15].
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 interferon-gamma 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
RIPK3 is an essential regulator of TNF-induced necrosis.
Species:  Mouse
Tissue: 
References:  2,5,16
Physiological Consequences of Altering Gene Expression
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 Medicinal Chemistry Letters, 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. Vince JE, Silke J. (2016) The intersection of cell death and inflammasome activation. Cell. Mol. Life Sci., 73 (11-12): 2349-67. [PMID:27066895]

15. 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]

16. 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]

17. 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 06/06/2019. Accessed on 23/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2191.