Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTAIQSN)

• DTT Name: Receptor-interacting protein 1 (RIPK1)
• Synonyms: Receptor-interacting serine/threonine-protein kinase 1; RIP1; RIP-1; RIP; Cell death protein RIP
• Gene Name: RIPK1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: RIPK1_HUMAN
• TTD ID: T99340
• EC Number: EC 2.7.11.1
• Sequence:
  MQPDMSLNVIKMKSSDFLESAELDSGGFGKVSLCFHRTQGLMIMKTVYKGPNCIEHNEAL
  LEEAKMMNRLRHSRVVKLLGVIIEEGKYSLVMEYMEKGNLMHVLKAEMSTPLSVKGRIIL
  EIIEGMCYLHGKGVIHKDLKPENILVDNDFHIKIADLGLASFKMWSKLNNEEHNELREVD
  GTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMC
  IKSGNRPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYLSQLEESVEED
  VKSLKKEYSNENAVVKRMQSLQLDCVAVPSSRSNSATEQPGSLHSSQGLGMGPVEESWFA
  PSLEHPQEENEPSLQSKLQDEANYHLYGSRMDRQTKQQPRQNVAYNREEERRRRVSHDPF
  AQQRPYENFQNTEGKGTAYSSAASHGNAVHQPSGLTSQPQVLYQNNGLYSSHGFGTRPLD
  PGTAGPRVWYRPIPSHMPSLHNIPVPETNYLGNTPTMPFSSLPPTDESIKYTIYNSTGIQ
  IGAYNYMEIGGTSSSLLDSTNTNFKEEPAAKYQAIFDNTTSLTDKHLDPIRENLGKHWKN
  CARKLGFTQSQIDEIDHDYERDGLKEKVYQMLQKWVMREGIKGATVGKLAQALHQCSRID
  LLSSLIYVSQN
• Function: Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex. Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage.
• KEGG Pathway:
  NF-kappa B signaling pathway (hsa04064)
  Apoptosis (hsa04210)
  Necroptosis (hsa04217)
  Toll-like receptor signaling pathway (hsa04620)
  NOD-like receptor signaling pathway (hsa04621)
  RIG-I-like receptor signaling pathway (hsa04622)
  Cytosolic DNA-sensing pathway (hsa04623)
  TNF signaling 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 NFkappaB 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)
  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 DTT

8 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
DNL758	DM89D6C	Cutaneous lupus erythematosus	EB5Z	Phase 2	[2]
Eclitasertib	DM2O8VW	Ulcerative colitis	DD71	Phase 2	[3]
GSK2982772	DM7HNFV	Plaque psoriasis	EA90.0	Phase 2	[1]
SAR443820	DMNCP7B	Amyotrophic lateral sclerosis	8B60.0	Phase 2	[4]
GSK3145095	DM059OH	Pancreatic cancer	2C10	Phase 1/2	[5]
DNL104	DMOSCQ9	Alzheimer disease	8A20	Phase 1	[6]
DNL747	DMNSC0O	Alzheimer disease	8A20	Phase 1	[2]
R552	DM5XCRQ	Nervous system paraneoplastic or autoimmune disorders	8E4A.1	Phase 1	[2]

3 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Tricyclic compound 10	DMV1RQX	N. A.	N. A.	Patented	[7]
Tricyclic compound 8	DMZI8GK	N. A.	N. A.	Patented	[7]
Tricyclic compound 9	DMF5E6U	N. A.	N. A.	Patented	[7]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GNE684	DMXVHOQ	Inflammation	1A00-CA43.1	Preclinical	[8]

4 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GSK'963	DMNOU59	Myeloid leukaemia	2B33.1	Investigative	[9]
PK68	DMIUZGY	Inflammation	1A00-CA43.1	Investigative	[10]
PMID24900635C21	DM1QDG0	Discovery agent	N.A.	Investigative	[11]
RIPA-56	DMYIQRK	Non-alcoholic fatty liver disease	DB92	Investigative	[12]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target. Nat Rev Drug Discov. 2020 Aug;19(8):553-571.
• [3] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2023. Adis Insight
• [4] ClinicalTrials.gov (NCT05237284) A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of SAR443820 in Adult Participants With Amyotrophic Lateral Sclerosis, Followed by an Open-label Extension. U.S.National Institutes of Health.
• [5] Identification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic Cancer. ACS Med Chem Lett. 2019 May 9;10(6):857-862.
• [6] DNL104, a Centrally Penetrant RIPK1 Inhibitor, Inhibits RIP1 Kinase Phosphorylation in a Randomized Phase I Ascending Dose Study in Healthy Volunteers. Clin Pharmacol Ther. 2020 Feb;107(2):406-414.
• [7] Necroptosis inhibitors as therapeutic targets in inflammation mediated disorders - a review of the current literature and patents.Expert Opin Ther Pat. 2016 Nov;26(11):1239-1256.
• [8] Impaired RIPK1 ubiquitination sensitizes mice to TNF toxicity and inflammatory cell death. Cell Death Differ. 2021 Mar;28(3):985-1000.
• [9] Characterization of GSK'963: a structurally distinct, potent and selective inhibitor of RIP1 kinase. Cell Death Discov. 2015 Jul 27;1:15009.
• [10] Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis. Cell Death Dis. 2019 Jun 24;10(7):493.
• [11] Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis. ACS Med Chem Lett. 2013 Nov 4;4(12):1238-43.
• [12] Inhibition of receptor-interacting protein kinase 1 improves experimental non-alcoholic fatty liver disease. J Hepatol. 2020 Apr;72(4):627-635.