Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC41R1E)

• DOT Name: Receptor-interacting serine/threonine-protein kinase 1 (RIPK1)
• Synonyms: EC 2.7.11.1; Cell death protein RIP; Receptor-interacting protein 1; RIP-1
• Gene Name: RIPK1
• Related Disease:
  Autoinflammation with episodic fever and lymphadenopathy
  Immunodeficiency 57
  Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome
• UniProt ID: RIPK1_HUMAN
• PDB ID: 4ITH; 4ITI; 4ITJ; 4NEU; 5HX6; 5TX5; 5V7Z; 6AC5; 6C3E; 6C4D; 6HHO; 6NW2; 6NYH; 6OCQ; 6R5F; 6RLN; 7CJB; 7FCZ; 7FD0; 7XMK; 7YDX
• EC Number: 2.7.11.1
• Pfam ID: PF00531 ; PF07714
• Sequence:
  MQPDMSLNVIKMKSSDFLESAELDSGGFGKVSLCFHRTQGLMIMKTVYKGPNCIEHNEAL
  LEEAKMMNRLRHSRVVKLLGVIIEEGKYSLVMEYMEKGNLMHVLKAEMSTPLSVKGRIIL
  EIIEGMCYLHGKGVIHKDLKPENILVDNDFHIKIADLGLASFKMWSKLNNEEHNELREVD
  GTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMC
  IKSGNRPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYLSQLEESVEED
  VKSLKKEYSNENAVVKRMQSLQLDCVAVPSSRSNSATEQPGSLHSSQGLGMGPVEESWFA
  PSLEHPQEENEPSLQSKLQDEANYHLYGSRMDRQTKQQPRQNVAYNREEERRRRVSHDPF
  AQQRPYENFQNTEGKGTAYSSAASHGNAVHQPSGLTSQPQVLYQNNGLYSSHGFGTRPLD
  PGTAGPRVWYRPIPSHMPSLHNIPVPETNYLGNTPTMPFSSLPPTDESIKYTIYNSTGIQ
  IGAYNYMEIGGTSSSLLDSTNTNFKEEPAAKYQAIFDNTTSLTDKHLDPIRENLGKHWKN
  CARKLGFTQSQIDEIDHDYERDGLKEKVYQMLQKWVMREGIKGATVGKLAQALHQCSRID
  LLSSLIYVSQN
• Function: Serine-threonine kinase which is a key regulator of TNF-mediated apoptosis, necroptosis and inflammatory pathways. Exhibits kinase activity-dependent functions that regulate cell death and kinase-independent scaffold functions regulating inflammatory signaling and cell survival. Has kinase-independent scaffold functions: upon binding of TNF to TNFR1, RIPK1 is recruited to the TNF-R1 signaling complex (TNF-RSC also known as complex I) where it acts as a scaffold protein promoting cell survival, in part, by activating the canonical NF-kappa-B pathway. Kinase activity is essential to regulate necroptosis and apoptosis, two parallel forms of cell death: upon activation of its protein kinase activity, regulates assembly of two death-inducing complexes, namely complex IIa (RIPK1-FADD-CASP8), which drives apoptosis, and the complex IIb (RIPK1-RIPK3-MLKL), which drives necroptosis. RIPK1 is required to limit CASP8-dependent TNFR1-induced apoptosis. In normal conditions, RIPK1 acts as an inhibitor of RIPK3-dependent necroptosis, a process mediated by RIPK3 component of complex IIb, which catalyzes phosphorylation of MLKL upon induction by ZBP1. Inhibits RIPK3-mediated necroptosis via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis. Required to inhibit apoptosis and necroptosis during embryonic development: acts by preventing the interaction of TRADD with FADD thereby limiting aberrant activation of CASP8. In addition to apoptosis and necroptosis, also involved in inflammatory response by promoting transcriptional production of pro-inflammatory cytokines, such as interleukin-6 (IL6). Phosphorylates RIPK3: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade. Required for ZBP1-induced NF-kappa-B activation in response to DNA damage.
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  Apoptosis (hsa04210)
  Necroptosis (hsa04217)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Cytosolic D.-sensing pathway (hsa04623)
  TNF sig.ling pathway (hsa04668)
  Alcoholic liver disease (hsa04936)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Hepatitis C (hsa05160)
  Human cytomegalovirus infection (hsa05163)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  TICAM1, RIP1-mediated IKK complex recruitment (R-HSA-168927)
  RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476)
  TRIF-mediated programmed cell death (R-HSA-2562578)
  TRP channels (R-HSA-3295583)
  Regulation by c-FLIP (R-HSA-3371378)
  RIPK1-mediated regulated necrosis (R-HSA-5213460)
  CASP8 activity is inhibited (R-HSA-5218900)
  TNFR1-induced proapoptotic signaling (R-HSA-5357786)
  Regulation of TNFR1 signaling (R-HSA-5357905)
  TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956)
  Regulation of necroptotic cell death (R-HSA-5675482)
  Ub-specific processing proteases (R-HSA-5689880)
  Ovarian tumor domain proteases (R-HSA-5689896)
  Dimerization of procaspase-8 (R-HSA-69416)
  TNF signaling (R-HSA-75893)
  TLR3-mediated TICAM1-dependent programmed cell death (R-HSA-9013957)
  NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 (R-HSA-933543)
  IKK complex recruitment mediated by RIP1 (R-HSA-937041)
  Potential therapeutics for SARS (R-HSA-9679191)
  Microbial modulation of RIPK1-mediated regulated necrosis (R-HSA-9686347)
  SARS-CoV-1-mediated effects on programmed cell death (R-HSA-9692913)
  Defective RIPK1-mediated regulated necrosis (R-HSA-9693928)
  Caspase activation via Death Receptors in the presence of ligand (R-HSA-140534)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoinflammation with episodic fever and lymphadenopathy	DIS7FHSU	Strong	Autosomal dominant	[1]
Immunodeficiency 57	DISBN7VE	Strong	Autosomal recessive	[2]
Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome	DISGS7X3	Supportive	Autosomal recessive	[2]

26 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[13]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[14]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[15]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[16]
Nefazodone	DM4ZS8M	Approved	Nefazodone increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[3]
Phenylephrine	DMZHUO5	Approved	Phenylephrine increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[20]
GSK618334	DMJPXZ4	Phase 1	GSK618334 increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[22]
WIN-55212-2	DMACBIW	Terminated	WIN-55212-2 decreases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[24]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[26]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[27]
Apicidin	DM83WVF	Investigative	Apicidin decreases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[29]
Acacetin	DMQOB0X	Investigative	Acacetin increases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[30]
Octanedioic acid bis-hydroxyamide	DMJNQ9K	Investigative	Octanedioic acid bis-hydroxyamide decreases the expression of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[29]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the cleavage of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[25]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[23]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the phosphorylation of Receptor-interacting serine/threonine-protein kinase 1 (RIPK1).	[28]

References

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• [3] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
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• [17] 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.
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