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receptor interacting serine/threonine kinase 2

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2190

Nomenclature: receptor interacting serine/threonine kinase 2

Abbreviated Name: RIPK2

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 - 540 8q21.3 RIPK2 receptor interacting serine/threonine kinase 2
Mouse - 539 4 6.7 cM Ripk2 receptor (TNFRSF)-interacting serine-threonine kinase 2
Rat - 539 5 q13 Ripk2 receptor-interacting serine-threonine kinase 2
Previous and Unofficial Names Click here for help
CARD3 | CARDIAK | CCK | RICK | RIP2
Database Links Click here for help
Alphafold O43353 (Hs), P58801 (Mm)
BRENDA 2.7.11.1
ChEMBL Target CHEMBL5014 (Hs), CHEMBL4296021 (Mm)
Ensembl Gene ENSG00000104312 (Hs), ENSMUSG00000041135 (Mm), ENSRNOG00000009389 (Rn)
Entrez Gene 8767 (Hs), 192656 (Mm), 362491 (Rn)
Human Protein Atlas ENSG00000104312 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:8767 (Hs), mmu:192656 (Mm), rno:362491 (Rn)
OMIM 603455 (Hs)
Pharos O43353 (Hs)
RefSeq Nucleotide NM_003821 (Hs), NM_138952 (Mm), NM_001191865 (Rn)
RefSeq Protein NP_003812 (Hs), NP_620402 (Mm), NP_001178794 (Rn)
SynPHARM 83541 (in complex with GSK583)
UniProtKB O43353 (Hs), P58801 (Mm)
Wikipedia RIPK2 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  RIP2 Kinase Catalytic Domain complex with 2(4[(1,3benzothiazol5yl)amino]6(2methylpropane2sulfonyl)quinazolin7yl)oxy)ethyl phosphate
PDB Id:  6RN8
Ligand:  RIPK2 inhibitor 3
Resolution:  2.69Å
Species:  Human
References:  5
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
ZAK inhibitor 6p Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.2 pKd 15
⤷ pKd 7.2 (Kd 5.7x10-8 M) [15]
GSK583 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Rn Inhibition 8.7 pIC50 6
⤷ pIC50 8.7 (IC50 2x10-9 M) [6]
RIPK2 inhibitor 5 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Rn Inhibition 8.7 pIC50 5
⤷ pIC50 8.7 (IC50 2x10-9 M) [5]
Description: Determined in a fluorescence polarisationassay.
RIPK2 inhibitor 8 Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Inhibition 8.5 pIC50 7
⤷ pIC50 8.5 (IC50 3x10-9 M) [7]
GSK583 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.3 pIC50 6
⤷ pIC50 8.3 (IC50 5x10-9 M) [6]
RIPK2 inhibitor 5 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.3 pIC50 5
⤷ pIC50 8.3 (IC50 5x10-9 M) [5]
Description: Determined in a fluorescence polarisation assay.
OD36 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.3 pIC50 12
⤷ pIC50 8.3 (IC50 5.3x10-9 M) [12]
ponatinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.8 pIC50 9
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [9]
Description: Inhibition of recombinant RIPK2 in an in vitro ADP-Glo assay (Promega).
Src kinase inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.6 pIC50 2
⤷ pIC50 7.6 (IC50 2.6x10-8 M) [2]
PN10 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.8 pIC50 9
⤷ pIC50 5.8 (IC50 1.4x10-6 M) [9]
Description: Inhibition of recombinant human RIPK2 using ADP-Glo assay.
AS3334034 Small molecule or natural product Rn Inhibition - - 13
⤷ [13]
View species-specific inhibitor tables
DiscoveRx KINOMEscan® screen Click here for help
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: 3,14
Key to terms and symbols Click column headers to sort
Target used in screen: RIPK2
Ligand Sp. Type Action Value Parameter
vandetanib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 8.3 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.8 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.7 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 7.6 pKd
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.5 pKd
PP-242 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.1 pKd
cediranib Small molecule or natural product Hs Inhibitor Inhibition 7.0 pKd
Ki-20227 Small molecule or natural product Hs Inhibitor Inhibition 6.5 pKd
canertinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 6.5 pKd
PLX-4720 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 1,4
Key to terms and symbols Click column headers to sort
Target used in screen: RIPK2/RIPK2
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
K-252a Small molecule or natural product Hs Inhibitor Inhibition 11.4 5.0 3.0
dorsomorphin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 15.9 14.0 7.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 19.7 16.0 29.0
alsterpaullone 2-cyanoethyl Small molecule or natural product Hs Inhibitor Inhibition 21.5 18.0 10.0
vandetanib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 23.4
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 25.2
Lck inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 28.6 21.0 15.0
TWS119 Small molecule or natural product Hs Inhibitor Inhibition 30.5 18.0 11.0
AG 1024 Small molecule or natural product Hs Inhibitor Inhibition 32.8 26.0 16.0
PD 169316 Small molecule or natural product Hs Inhibitor Inhibition 32.8 19.0 25.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
RIPK2 is involved in innate immune responses, mediating pro-inflammatory signaling from the bacterial peptidoglycan-sensing NOD1/NOD2 subfamily of innate immune pattern recognition receptors (PRRs) and signalling downstream from the Toll-like receptor (TLR) family of PRRs. Further evidence suggesting an inflammatory role is the targeting of RIPK2 (along with RIPK1/3) by the IAP family E3 ubiquitin ligases (enzymes playing a critical role in innate immunity) [10]. RIPK2 may play a role in driving a range of chronic inflammatory granulomatous diseases (e.g. either loss-of-function of NOD2 or hyperactivation of the NOD2 pathway may contribute to IBD) [8], and since it shares common functionality with RIPK1 and RIPK3, may be involved in necroptosis (a type of programmed cell death, mechanistically and morphologically distinct from apoptosis) [11].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Immuno Process:  Immune system development
Immuno Process:  Chemotaxis & migration

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, Klevernic I, Arthur JS, Alessi DR, Cohen P. (2007) The selectivity of protein kinase inhibitors: a further update. Biochem J, 408 (3): 297-315. [PMID:17850214]

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. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

5. Haile PA, Casillas LN, Votta BJ, Wang GZ, Charnley AK, Dong X, Bury MJ, Romano JJ, Mehlmann JF, King BW et al.. (2019) Discovery of a First-in-Class Receptor Interacting Protein 2 (RIP2) Kinase Specific Clinical Candidate, 2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl Dihydrogen Phosphate, for the Treatment of Inflammatory Diseases. J Med Chem, 62 (14): 6482-6494. [PMID:31265286]

6. Haile PA, Votta BJ, Marquis RW, Bury MJ, Mehlmann JF, Singhaus Jr R, Charnley AK, Lakdawala AS, Convery MA, Lipshutz DB et al.. (2016) The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase. J Med Chem, 59 (10): 4867-80. [PMID:27109867]

7. He X, Da Ros S, Nelson J, Zhu X, Jiang T, Okram B, Jiang S, Michellys PY, Iskandar M, Espinola S et al.. (2017) Identification of Potent and Selective RIPK2 Inhibitors for the Treatment of Inflammatory Diseases. ACS Med Chem Lett, 8 (10): 1048-1053. [PMID:29057049]

8. 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]

9. 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]

10. Oberst A. (2016) Death in the fast lane: what's next for necroptosis?. FEBS J, 283 (14): 2616-25. [PMID:26395133]

11. 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]

12. Tigno-Aranjuez JT, Benderitter P, Rombouts F, Deroose F, Bai X, Mattioli B, Cominelli F, Pizarro TT, Hoflack J, Abbott DW. (2014) In vivo inhibition of RIPK2 kinase alleviates inflammatory disease. J Biol Chem, 289 (43): 29651-64. [PMID:25213858]

13. Wada Y, Kondo M, Sakairi K, Nagashima A, Tokita K, Tominaga H, Tomiyama H, Ishikawa T. (2020) Renoprotective Effects of a Novel Receptor-Interacting Protein Kinase 2 Inhibitor, AS3334034, in Uninephrectomized Adriamycin-Induced Chronic Kidney Disease Rats. J Pharmacol Exp Ther, 374 (3): 428-437. [PMID:32561685]

14. 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]

15. Yang J, Shibu MA, Kong L, Luo J, BadrealamKhan F, Huang Y, Tu ZC, Yun CH, Huang CY, Ding K et al.. (2020) Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors. J Med Chem, 63 (5): 2114-2130. [PMID:31244114]

How to cite this page

Receptor interacting protein kinase (RIPK) family: receptor interacting serine/threonine kinase 2. Last modified on 22/06/2020. Accessed on 10/12/2023. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2190.