Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL1D484)

DOT Name	Receptor-interacting serine/threonine-protein kinase 3 (RIPK3)
Synonyms	EC 2.7.11.1; RIP-like protein kinase 3; Receptor-interacting protein 3; RIP-3
Gene Name	RIPK3
Related Disease	Advanced cancer ( ) Breast cancer ( ) Breast carcinoma ( ) Acute myelogenous leukaemia ( ) Adenocarcinoma ( ) Adult glioblastoma ( ) Arteriosclerosis ( ) Arthritis ( ) Atherosclerosis ( ) Bone osteosarcoma ( ) Carcinoma of esophagus ( ) Cardiac failure ( ) Cardiomyopathy ( ) Colon cancer ( ) Colon carcinoma ( ) Congestive heart failure ( ) Esophageal cancer ( ) Fatty liver disease ( ) Glioblastoma multiforme ( ) Glioma ( ) Lung cancer ( ) Lung carcinoma ( ) Myocardial infarction ( ) Neoplasm ( ) Neoplasm of esophagus ( ) Osteosarcoma ( ) Parkinson disease ( ) Pneumonia ( ) Small-cell lung cancer ( ) Subarachnoid hemorrhage ( ) Systemic lupus erythematosus ( ) Ulcerative colitis ( ) Amyotrophic lateral sclerosis ( ) Calcinosis ( ) Familial tumoral calcinosis ( ) Heart valve disorder ( ) Influenza ( ) Pulmonary fibrosis ( ) Colorectal carcinoma ( ) Inflammation ( ) Pneumonitis ( ) Abdominal aortic aneurysm ( ) Bacterial infection ( ) Hepatitis ( ) Inflammatory bowel disease ( ) Melanoma ( )
UniProt ID	RIPK3_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	5V7Z; 5ZCK; 7DA4; 7DAC; 7MON; 7MX3
EC Number	2.7.11.1
Pfam ID	PF00069 ; PF12721
Sequence	MSCVKLWPSGAPAPLVSIEELENQELVGKGGFGTVFRAQHRKWGYDVAVKIVNSKAISRE VKAMASLDNEFVLRLEGVIEKVNWDQDPKPALVTKFMENGSLSGLLQSQCPRPWPLLCRL LKEVVLGMFYLHDQNPVLLHRDLKPSNVLLDPELHVKLADFGLSTFQGGSQSGTGSGEPG GTLGYLAPELFVNVNRKASTASDVYSFGILMWAVLAGREVELPTEPSLVYEAVCNRQNRP SLAELPQAGPETPGLEGLKELMQLCWSSEPKDRPSFQECLPKTDEVFQMVENNMNAAVST VKDFLSQLRSSNRRFSIPESGQGGTEMDGFRRTIENQHSRNDVMVSEWLNKLNLEEPPSS VPKKCPSLTKRSRAQEEQVPQAWTAGTSSDSMAQPPQTPETSTFRNQMPSPTSTGTPSPG PRGNQGAERQGMNWSCRTPEPNPVTGRPLVNIYNCSGVQVGDNNYLTMQQTTALPTWGLA PSGKGRGLQHPPPVGSQEGPKDPEAWSRPQGWYNHSGK
Function	Serine/threonine-protein kinase that activates necroptosis and apoptosis, two parallel forms of cell death. Necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members, is triggered by RIPK3 following activation by ZBP1. Activated RIPK3 forms a necrosis-inducing complex and mediates phosphorylation of MLKL, promoting MLKL localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage. In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: following ZBP1 activation, which senses double-stranded Z-RNA structures, nuclear RIPK3 catalyzes phosphorylation and activation of MLKL, promoting disruption of the nuclear envelope and leakage of cellular DNA into the cytosol. Also regulates apoptosis: apoptosis depends on RIPK1, FADD and CASP8, and is independent of MLKL and RIPK3 kinase activity. Phosphorylates RIPK1: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. In some cell types, also able to restrict viral replication by promoting cell death-independent responses. In response to Zika virus infection in neurons, promotes a cell death-independent pathway that restricts viral replication: together with ZBP1, promotes a death-independent transcriptional program that modifies the cellular metabolism via up-regulation expression of the enzyme ACOD1/IRG1 and production of the metabolite itaconate. Itaconate inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes. RIPK3 binds to and enhances the activity of three metabolic enzymes: GLUL, GLUD1, and PYGL. These metabolic enzymes may eventually stimulate the tricarboxylic acid cycle and oxidative phosphorylation, which could result in enhanced ROS production ; (Microbial infection) In case of herpes simplex virus 1/HHV-1 infection, forms heteromeric amyloid structures with HHV-1 protein RIR1/ICP6 which may inhibit RIPK3-mediated necroptosis, thereby preventing host cell death pathway and allowing viral evasion.
Tissue Specificity	Highly expressed in the pancreas. Detected at lower levels in heart, placenta, lung and kidney.; [Isoform 3]: Expression is significantly increased in colon and lung cancers.
KEGG Pathway	Necroptosis (hsa04217 ) NOD-like receptor sig.ling pathway (hsa04621 ) Cytosolic D.-sensing pathway (hsa04623 ) TNF sig.ling pathway (hsa04668 ) Salmonella infection (hsa05132 )
Reactome Pathway	RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476 ) TRIF-mediated programmed cell death (R-HSA-2562578 ) TRP channels (R-HSA-3295583 ) RIPK1-mediated regulated necrosis (R-HSA-5213460 ) Regulation of necroptotic cell death (R-HSA-5675482 ) TLR3-mediated TICAM1-dependent programmed cell death (R-HSA-9013957 ) IKK complex recruitment mediated by RIP1 (R-HSA-937041 ) Microbial modulation of RIPK1-mediated regulated necrosis (R-HSA-9686347 ) SARS-CoV-1-mediated effects on programmed cell death (R-HSA-9692913 ) SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916 ) TICAM1, RIP1-mediated IKK complex recruitment (R-HSA-168927 )

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Definitive	Biomarker	[2]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[4]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Arthritis	DIST1YEL	Strong	Biomarker	[7]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[8]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[9]
Cardiac failure	DISDC067	Strong	Genetic Variation	[10]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[11]
Colon cancer	DISVC52G	Strong	Altered Expression	[1]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[1]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[10]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[9]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[5]
Glioma	DIS5RPEH	Strong	Biomarker	[13]
Lung cancer	DISCM4YA	Strong	Biomarker	[14]
Lung carcinoma	DISTR26C	Strong	Biomarker	[14]
Myocardial infarction	DIS655KI	Strong	Biomarker	[15]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[9]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[8]
Parkinson disease	DISQVHKL	Strong	Biomarker	[17]
Pneumonia	DIS8EF3M	Strong	Biomarker	[18]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[19]
Subarachnoid hemorrhage	DISI7I8Y	Strong	Biomarker	[20]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[21]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[22]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[23]
Calcinosis	DISQP4OR	moderate	Biomarker	[24]
Familial tumoral calcinosis	DISYJZKG	moderate	Biomarker	[24]
Heart valve disorder	DIS84O7T	moderate	Biomarker	[24]
Influenza	DIS3PNU3	moderate	Biomarker	[25]
Pulmonary fibrosis	DISQKVLA	moderate	Altered Expression	[26]
Colorectal carcinoma	DIS5PYL0	Disputed	Biomarker	[1]
Inflammation	DISJUQ5T	Disputed	Biomarker	[27]
Pneumonitis	DIS88E0K	Disputed	Biomarker	[18]
Abdominal aortic aneurysm	DISD06OF	Limited	Genetic Variation	[28]
Bacterial infection	DIS5QJ9S	Limited	Biomarker	[29]
Hepatitis	DISXXX35	Limited	Biomarker	[12]
Inflammatory bowel disease	DISGN23E	Limited	Biomarker	[30]
Melanoma	DIS1RRCY	Limited	Biomarker	[2]
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⏷ Show the Full List of 46 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3).	[31]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3).	[39]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the phosphorylation of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3).	[41]
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9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3).	[32]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3).	[33]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3).	[35]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3).	[36]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3).	[37]
Phenylephrine	DMZHUO5	Approved	Phenylephrine increases the expression of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3).	[38]
GSK618334	DMJPXZ4	Phase 1	GSK618334 increases the expression of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3).	[40]
CHLORANIL	DMCHGF1	Investigative	CHLORANIL increases the expression of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3).	[42]
Acacetin	DMQOB0X	Investigative	Acacetin increases the expression of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3).	[43]
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⏷ Show the Full List of 9 Drug(s)

References

1	RIP3 promotes colitis-associated colorectal cancer by controlling tumor cell proliferation and CXCL1-induced immune suppression.Theranostics. 2019 Jun 2;9(12):3659-3673. doi: 10.7150/thno.32126. eCollection 2019.
2	Pro-necrotic molecules impact local immunosurveillance in human breast cancer.Oncoimmunology. 2017 Apr 17;6(4):e1299302. doi: 10.1080/2162402X.2017.1299302. eCollection 2017.
3	Sensitizing acute myeloid leukemia cells to induced differentiation by inhibiting the RIP1/RIP3 pathway.Leukemia. 2017 May;31(5):1154-1165. doi: 10.1038/leu.2016.287. Epub 2016 Oct 17.
4	Receptor-interacting protein kinase 3 as a predictive adjuvant chemotherapy marker after lung adenocarcinoma resection.Ann Transl Med. 2019 Feb;7(3):42. doi: 10.21037/atm.2018.12.65.
5	RIP3 antagonizes a TSC2-mediated pro-survival pathway in glioblastoma cell death.Biochim Biophys Acta Mol Cell Res. 2017 Jan;1864(1):113-124. doi: 10.1016/j.bbamcr.2016.10.014. Epub 2016 Oct 27.
6	Exogenous hydrogen sulfide protects human umbilical vein endothelial cells against high glucoseinduced injury by inhibiting the necroptosis pathway.Int J Mol Med. 2018 Mar;41(3):1477-1486. doi: 10.3892/ijmm.2017.3330. Epub 2017 Dec 19.
7	A20 prevents inflammasome-dependent arthritis by inhibiting macrophage necroptosis through its ZnF7 ubiquitin-binding domain.Nat Cell Biol. 2019 Jun;21(6):731-742. doi: 10.1038/s41556-019-0324-3. Epub 2019 May 13.
8	Combined analysis of DNA methylation and gene expression profiles of osteosarcoma identified several prognosis signatures.Gene. 2018 Apr 15;650:7-14. doi: 10.1016/j.gene.2018.01.093. Epub 2018 Jan 31.
9	Down-regulation of RIP3 potentiates cisplatin chemoresistance by triggering HSP90-ERK pathway mediated DNA repair in esophageal squamous cell carcinoma.Cancer Lett. 2018 Apr 1;418:97-108. doi: 10.1016/j.canlet.2018.01.022. Epub 2018 Jan 10.
10	A common variant of RIP3 promoter region is associated with poor prognosis in heart failure patients by influencing SOX17 binding.J Cell Mol Med. 2019 Aug;23(8):5317-5328. doi: 10.1111/jcmm.14408. Epub 2019 May 31.
11	Therapeutic contribution of melatonin to the treatment of septic cardiomyopathy: A novel mechanism linking Ripk3-modified mitochondrial performance and endoplasmic reticulum function.Redox Biol. 2019 Sep;26:101287. doi: 10.1016/j.redox.2019.101287. Epub 2019 Jul 27.
12	Activated TNF-/RIPK3 signaling is involved in prolonged high fat diet-stimulated hepatic inflammation and lipid accumulation: inhibition by dietary fisetin intervention.Food Funct. 2019 Mar 20;10(3):1302-1316. doi: 10.1039/c8fo01615a.
13	RIP1 and RIP3 contribute to shikonin-induced DNA double-strand breaks in glioma cells via increase of intracellular reactive oxygen species.Cancer Lett. 2017 Apr 1;390:77-90. doi: 10.1016/j.canlet.2017.01.004. Epub 2017 Jan 17.
14	HS-173 as a novel inducer of RIP3-dependent necroptosis in lung cancer.Cancer Lett. 2019 Mar 1;444:94-104. doi: 10.1016/j.canlet.2018.12.006. Epub 2018 Dec 21.
15	Simultaneous Suppression of Multiple Programmed Cell Death Pathways by miRNA-105 in Cardiac Ischemic Injury.Mol Ther Nucleic Acids. 2019 Mar 1;14:438-449. doi: 10.1016/j.omtn.2018.12.015. Epub 2019 Jan 10.
16	RIPK3-Induced Inflammation by I-MDSCs Promotes Intestinal Tumors.Cancer Res. 2019 Apr 1;79(7):1587-1599. doi: 10.1158/0008-5472.CAN-18-2153. Epub 2019 Feb 20.
17	RIP1/RIP3/MLKL mediates dopaminergic neuron necroptosis in a mouse model of Parkinson disease.Lab Invest. 2020 Mar;100(3):503-511. doi: 10.1038/s41374-019-0319-5. Epub 2019 Sep 10.
18	TREM-1 Attenuates RIPK3-mediated Necroptosis in Hyperoxia-induced Lung Injury in Neonatal Mice.Am J Respir Cell Mol Biol. 2019 Mar;60(3):308-322. doi: 10.1165/rcmb.2018-0219OC.
19	Sinoporphyrin Sodium-Mediated Sonodynamic Therapy Inhibits RIP3 Expression and Induces Apoptosis in the H446 Small Cell Lung Cancer Cell Line.Cell Physiol Biochem. 2018;51(6):2938-2954. doi: 10.1159/000496045. Epub 2018 Dec 14.
20	RIP3 participates in early brain injury after experimental subarachnoid hemorrhage in rats by inducing necroptosis.Neurobiol Dis. 2019 Sep;129:144-158. doi: 10.1016/j.nbd.2019.05.004. Epub 2019 May 10.
21	Necroptotic cell binding of (2) -glycoprotein I provides a potential autoantigenic stimulus in systemic lupus erythematosus.Immunol Cell Biol. 2019 Oct;97(9):799-814. doi: 10.1111/imcb.12279. Epub 2019 Jun 12.
22	Expression of receptor interacting protein 3 and mixed lineage kinase domain-like protein-key proteins in necroptosis is upregulated in ulcerative colitis.Ann Palliat Med. 2019 Sep;8(4):483-489. doi: 10.21037/apm.2019.07.04. Epub 2019 Aug 12.
23	Necroptosis is dispensable for motor neuron degeneration in a mouse model of ALS.Cell Death Differ. 2020 May;27(5):1728-1739. doi: 10.1038/s41418-019-0457-8. Epub 2019 Nov 19.
24	Raloxifene attenuates Gas6 and apoptosis in experimental aortic valve disease in renal failure.Am J Physiol Heart Circ Physiol. 2011 May;300(5):H1829-40. doi: 10.1152/ajpheart.00240.2010. Epub 2011 Feb 18.
25	RIP3 deficiency ameliorates inflammatory response in mice infected with influenza H7N9 virus infection.Oncotarget. 2017 Apr 25;8(17):27715-27724. doi: 10.18632/oncotarget.16016.
26	A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis.J Exp Med. 2019 Dec 2;216(12):2724-2735. doi: 10.1084/jem.20182351. Epub 2019 Oct 10.
27	RIP3 deficiency exacerbates inflammation in dextran sodium sulfate-induced ulcerative colitis mice model.Cell Biochem Funct. 2017 Apr;35(3):156-163. doi: 10.1002/cbf.3257. Epub 2017 Mar 2.
28	Identification of a novel class of RIP1/RIP3 dual inhibitors that impede cell death and inflammation in mouse abdominal aortic aneurysm models.Cell Death Dis. 2019 Mar 6;10(3):226. doi: 10.1038/s41419-019-1468-6.
29	High mobility group box 1 enables bacterial lipids to trigger receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis and apoptosis in mice.J Biol Chem. 2019 May 31;294(22):8872-8884. doi: 10.1074/jbc.RA118.007040. Epub 2019 Apr 18.
30	A RIPK3-PGE(2) Circuit Mediates Myeloid-Derived Suppressor Cell-Potentiated Colorectal Carcinogenesis.Cancer Res. 2018 Oct 1;78(19):5586-5599. doi: 10.1158/0008-5472.CAN-17-3962. Epub 2018 Jul 16.
31	Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
32	Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
33	Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
34	Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
35	Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals. Int J Mol Sci. 2021 Oct 12;22(20):11005. doi: 10.3390/ijms222011005.
36	Gallic acid protects against ethanol-induced hepatocyte necroptosis via an NRF2-dependent mechanism. Toxicol In Vitro. 2019 Jun;57:226-232. doi: 10.1016/j.tiv.2019.03.008. Epub 2019 Mar 7.
37	Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
38	Phenylephrine induces necroptosis and apoptosis in corneal epithelial cells dose- and time-dependently. Toxicology. 2019 Dec 1;428:152305. doi: 10.1016/j.tox.2019.152305. Epub 2019 Oct 9.
39	Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
40	FTY720 induces autophagy-related apoptosis and necroptosis in human glioblastoma cells. Toxicol Lett. 2015 Jul 2;236(1):43-59. doi: 10.1016/j.toxlet.2015.04.015. Epub 2015 May 1.
41	PGAM5 regulates DRP1-mediated mitochondrial fission/mitophagy flux in lipid overload-induced renal tubular epithelial cell necroptosis. Toxicol Lett. 2023 Jan 1;372:14-24. doi: 10.1016/j.toxlet.2022.10.003. Epub 2022 Oct 20.
42	Atypical Gasdermin D and Mixed Lineage Kinase Domain-like Protein Leakage Aggravates Tetrachlorobenzoquinone-Induced Nod-like Receptor Protein 3 Inflammasome Activation. Chem Res Toxicol. 2018 Dec 17;31(12):1418-1425. doi: 10.1021/acs.chemrestox.8b00306. Epub 2018 Nov 9.
43	Acacetin induces sustained ERK1/2 activation and RIP1-dependent necroptotic death in breast cancer cells. Toxicol Appl Pharmacol. 2023 Mar 1;462:116409. doi: 10.1016/j.taap.2023.116409. Epub 2023 Feb 3.