receptor interacting serine/threonine kinase 1 | Receptor interacting protein kinase (RIPK) family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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receptor interacting serine/threonine kinase 1

  Target has curated data in GtoImmuPdb

Target id: 2189

Nomenclature: receptor interacting serine/threonine kinase 1

Abbreviated Name: RIPK1

Family: Receptor interacting protein kinase (RIPK) family

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 671 6p25.2 RIPK1 receptor interacting serine/threonine kinase 1
Mouse - 656 13 A3.3 Ripk1 receptor (TNFRSF)-interacting serine-threonine kinase 1
Rat - 658 17 p12 Ripk1 receptor interacting serine/threonine kinase 1
Previous and Unofficial Names
RIP | Rip1 | receptor (TNFRSF)-interacting serine-threonine kinase 1
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of RIP1 kinase in complex with necrostatin-4
PDB Id:  4ITJ
Resolution:  1.8Å
Species:  Human
References:  22
Image of receptor 3D structure from RCSB PDB
Description:  X-ray structure of Receptor Interacting Protein 1 (RIP1)kinase domain with a 1-aminoisoquinoline inhibitor
PDB Id:  4NEU
Resolution:  2.57Å
Species:  Human
References:  7
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 Affinity Parameter Reference
RIPK1 inhibitor 22b Hs Inhibition 8.4 pKd 12
pKd 8.4 (Kd 4.4x10-9 M) [12]
Description: Binding affinity value.
necrostatin-1s Hs Inhibition 7.4 pKd 5
pKd 7.4 (Kd 3.7x10-8 M) [5]
Description: Affinity constant measured at 37oC.
6E11 Hs Inhibition 6.4 pKd 6
pKd 6.4 (Kd 4x10-7 M) [6]
Description: Binding constant measured at 37oC.
GSK963 Hs Inhibition 9.1 pIC50 1
pIC50 9.1 (IC50 8x10-10 M) [1]
Description: Inhibition of RIPK1 kinase activity in an ADP-Glo kinase assay measuring autophosphorylation of RIPK1 kinase domain in vitro; value calculated using a tight binding fit calculation.
GSK2982772 Hs Inhibition 9.0 pIC50 8
pIC50 9.0 (IC50 1x10-9 M) [8]
compound 21 [PMID: 24900635] Hs Inhibition 8.9 pIC50 7
pIC50 8.9 (IC50 1.3x10-9 M) [7]
RIPK1 inhibitor 22b Hs Inhibition 8.0 pIC50 12
pIC50 8.0 (IC50 1.1x10-8 M) [12]
Description: Inhibition of RIPK1 enzymatic activity in vitro determined using Eurofins' KinaseProfiler assay.
ponatinib Hs Inhibition 7.9 pIC50 14
pIC50 7.9 (IC50 1.2x10-8 M) [14]
Description: Inhibition of recombinant RIPK1 in an in vitro ADP-Glo assay (Promega).
RIPA-56 Hs Inhibition 7.9 pIC50 16
pIC50 7.9 (IC50 1.3x10-8 M) [16]
Description: Inhibition of RIPK1 enzymatic activity in vitro.
compound 27 [PMID: 24900635] Hs Inhibition 7.9 pIC50 7
pIC50 7.9 (IC50 1.3x10-8 M) [7]
Description: IN an ADP-glo assay that measures the ADP produced during autophosphorylation of RIPK1 catalytic domain.
PN10 Hs Inhibition 7.1 pIC50 14
pIC50 7.1 (IC50 9x10-8 M) [14]
Description: Inhibition of recombinant human RIPK1 using ADP-Glo assay.
necrostatin-1 Hs Inhibition 6.3 pIC50 4
pIC50 6.3 (IC50 4.9x10-7 M) [4]
Description: Measuring inhibition of cellular necrosis in TNFα-treated FADD-deficient Jurkat cells.
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 3,21

Key to terms and symbols Click column headers to sort
Target used in screen: RIPK1
Ligand Sp. Type Action Affinity Parameter
tozasertib Hs Inhibitor Inhibition 7.7 pKd
KW-2449 Hs Inhibitor Inhibition 7.2 pKd
AST-487 Hs Inhibitor Inhibition 6.7 pKd
JNJ-28312141 Hs Inhibitor Inhibition 6.6 pKd
pazopanib Hs Inhibitor Inhibition 6.6 pKd
dovitinib Hs Inhibitor Inhibition 6.5 pKd
sunitinib Hs Inhibitor Inhibition 6.4 pKd
foretinib Hs Inhibitor Inhibition 6.1 pKd
quizartinib Hs Inhibitor Inhibition 6.1 pKd
SU-14813 Hs Inhibitor Inhibition 5.9 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
RIPK1 and RIPK3 are involved in necroptosis and as such are critical regulators of inflammation and cell death [15,17-19]. RIPK1 and RIPK2 appear to be critical mediators of intestinal homeostasis and drivers of intestinal inflammation [9]. RIPK-targeting necroptosis inhibitors are being developed to target inflammation mediated disorders [10], including the development of novel therapeutics for the treatment of TNF-induced systemic inflammatory response syndrome (SIRS) and sepsis, as well as cancer [1,7,13,20]. RIPK1 inhibitors are also being evaluated in clinical trials for autoimmune diseases including psoriasis, rheumatoid arthritis and ulcerative colitis (e.g. GSK2982772).

In the immuno-oncology setting RIPK1 inhibitors are being investigated as adjuncts to checkpoint inhibiting drugs like pembrolizumab, with the goal of enhancing the anti-tumour immune system reactivating effects of checkpoint inhibition. For example, GlaxoSmithKline have an experimental RIPK1 inhibitor known by the research code GSK095, that has shown exactly this effect in preclinical models of pancreatic cancer, and which is about to enter Phase 1 trial in patients with advanced pancreatic ductal adenocarcinoma (as of November 2018).

There were two independent reports of human RIPK1 deficiency as a causaul factor in patients with severe immunodeficiency in 2018: Cuchet-Lourenço et al. [2] and Li et al. [11] identified biallelic loss-of-function mutations in RIPK1 genes of patients with primary immunodeficiency and notably, early-onset intestinal immune dysregulation amongst other signs and symptoms of immunodeficiency (recurrent infection, progressive polyarthritis, lymphopenia, altered cytokine production). These studies highlight the importance of RIPK1 function as a key regulator of human immune and intestinal homeostasis, and also raise awareness of the possible undesireable outcomes when targeting RIPK1 for therapeutic benefit.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 3 GO processes
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0034138 toll-like receptor 3 signaling pathway TAS
GO:0035666 TRIF-dependent toll-like receptor signaling pathway TAS
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0070231 T cell apoptotic process ISS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 4 GO processes
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0034138 toll-like receptor 3 signaling pathway TAS
GO:0035666 TRIF-dependent toll-like receptor signaling pathway TAS
GO:0045651 positive regulation of macrophage differentiation IMP
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes
GO:0045651 positive regulation of macrophage differentiation IMP
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 7 GO processes
GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway TAS
GO:0032757 positive regulation of interleukin-8 production IDA
GO:0032760 positive regulation of tumor necrosis factor production IDA
GO:0033209 tumor necrosis factor-mediated signaling pathway TAS
GO:0034612 response to tumor necrosis factor IMP
GO:0071356 cellular response to tumor necrosis factor IDA
click arrow to show/hide IEA associations
GO:1903265 positive regulation of tumor necrosis factor-mediated signaling pathway IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 3 GO processes
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0034138 toll-like receptor 3 signaling pathway TAS
GO:0035666 TRIF-dependent toll-like receptor signaling pathway TAS
Biologically Significant Variants
Type:  Truncation
Species:  Human
Description:  Deleterious RIPK1 mutation identified in patient with combined immunodeficiency associated with lymphopenia.
Amino acid change:  M318IfsTer194
Nucleotide change:  954delG
References:  11
Type:  Missense mutation
Species:  Human
Description:  Deleterious RIPK1 mutation identified in patient with primary immunodeficiency characterised by very early onset irritable bowel disease (VEO-IBD).
Amino acid change:  I615T
Nucleotide change:  1844T>C
References:  11
Type:  Missense mutation
Species:  Human
Description:  Deleterious RIPK1 mutation identified in 3 patients with primary immunodeficiency characterised by very early onset irritable bowel disease (VEO-IBD).
Amino acid change:  C601Y
Nucleotide change:  1802G>A
References:  11
Type:  Missense mutation
Species:  Human
Description:  Deleterious RIPK1 mutation identified in 2 patients with primary immunodeficiency characterised by very early onset irritable bowel disease (VEO-IBD).
Amino acid change:  T645M
Nucleotide change:  1934C>T
References:  11
Type:  Deletion
Species:  Human
Description:  Exon 4 deletion causing loss of RIPK1 expression in a patient with primary immunodeficiency.
References:  2
Type:  Insertion/deletion
Species:  Human
Description:  Intron 4 insertion/deletion leading to loss of functional RIPK1 expression in a patient with primary immunodeficiency.
References:  2
Type:  Truncation
Species:  Human
Description:  Deleterious RIPK1 mutation identified in patient with combined immunodeficiency associated with lymphopenia.
Amino acid change:  Y426*
Nucleotide change:  1278C>A
References:  11

References

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1. Berger SB, Harris P, Nagilla R, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M, Capriotti C, Ouellette M et al.. (2015) Characterization of GSK'963: a structurally distinct, potent and selective inhibitor of RIP1 kinase. Cell Death Discov, 1: 15009. [PMID:27551444]

2. Cuchet-Lourenço D, Eletto D, Wu C, Plagnol V, Papapietro O, Curtis J, Ceron-Gutierrez L, Bacon CM, Hackett S, Alsaleem B et al.. (2018) Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science, 361 (6404): 810-813. [PMID:30026316]

3. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

4. Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G et al.. (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol., 4 (5): 313-21. [PMID:18408713]

5. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S. (1998) Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc. Natl. Acad. Sci. U.S.A., 95 (19): 11211-6. [PMID:9736715]

6. Delehouzé C, Leverrier-Penna S, Le Cann F, Comte A, Jacquard-Fevai M, Delalande O, Desban N, Baratte B, Gallais I, Faurez F et al.. (2017) 6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury. Sci Rep, 7 (1): 12931. [PMID:29018243]

7. Harris PA, Bandyopadhyay D, Berger SB, Campobasso N, Capriotti CA, Cox JA, Dare L, Finger JN, Hoffman SJ, Kahler KM et al.. (2013) Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis. ACS Med Chem Lett, 4 (12): 1238-43. [PMID:24900635]

8. Harris PA, Berger SB, Jeong JU, Nagilla R, Bandyopadhyay D, Campobasso N, Capriotti CA, Cox JA, Dare L, Dong X et al.. (2017) Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases. J. Med. Chem., 60 (4): 1247-1261. [PMID:28151659]

9. Jun JC, Cominelli F, Abbott DW. (2013) RIP2 activity in inflammatory disease and implications for novel therapeutics. J. Leukoc. Biol., 94 (5): 927-32. [PMID:23794710]

10. 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]

11. Li Y, Führer M, Bahrami E, Socha P, Klaudel-Dreszler M, Bouzidi A, Liu Y, Lehle AS, Magg T, Hollizeck S et al.. (2019) Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases. Proc. Natl. Acad. Sci. U.S.A., 116 (3): 970-975. [PMID:30591564]

12. 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]

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

14. 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]

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

16. Ren Y, Su Y, Sun L, He S, Meng L, Liao D, Liu X, Ma Y, Liu C, Li S et al.. (2017) Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-Interacting Protein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome. J. Med. Chem., 60 (3): 972-986. [PMID:27992216]

17. 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]

18. 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]

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

20. 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]

21. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

22. Xie T, Peng W, Liu Y, Yan C, Maki J, Degterev A, Yuan J, Shi Y. (2013) Structural Basis of RIP1 Inhibition by Necrostatins. Structure, 21 (3): 493-9. [PMID:23473668]

How to cite this page

Receptor interacting protein kinase (RIPK) family: receptor interacting serine/threonine kinase 1. Last modified on 09/01/2019. Accessed on 25/05/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2189.