Target Information
| Target General Information | Top | |||||
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| Target ID |
T99340
(Former ID: TTDI03510)
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| Target Name |
Receptor-interacting protein 1 (RIPK1)
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| Synonyms |
Receptor-interacting serine/threonine-protein kinase 1; RIP1; RIP-1; RIP; Cell death protein RIP
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| Gene Name |
RIPK1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 8 Target-related Diseases | + | ||||
| 1 | Cutaneous lupus erythematosus [ICD-11: EB50-EB5Z] | |||||
| 2 | Psoriasis [ICD-11: EA90] | |||||
| 3 | Pancreatic cancer [ICD-11: 2C10] | |||||
| 4 | Alzheimer disease [ICD-11: 8A20] | |||||
| 5 | Motor neuron disease [ICD-11: 8B60] | |||||
| 6 | Nervous system paraneoplastic/autoimmune disorder [ICD-11: 8E4A] | |||||
| 7 | Rheumatoid arthritis [ICD-11: FA20] | |||||
| 8 | Ulcerative colitis [ICD-11: DD71] | |||||
| 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.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.1
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| Sequence |
MQPDMSLNVIKMKSSDFLESAELDSGGFGKVSLCFHRTQGLMIMKTVYKGPNCIEHNEAL
LEEAKMMNRLRHSRVVKLLGVIIEEGKYSLVMEYMEKGNLMHVLKAEMSTPLSVKGRIIL EIIEGMCYLHGKGVIHKDLKPENILVDNDFHIKIADLGLASFKMWSKLNNEEHNELREVD GTAKKNGGTLYYMAPEHLNDVNAKPTEKSDVYSFAVVLWAIFANKEPYENAICEQQLIMC IKSGNRPDVDDITEYCPREIISLMKLCWEANPEARPTFPGIEEKFRPFYLSQLEESVEED VKSLKKEYSNENAVVKRMQSLQLDCVAVPSSRSNSATEQPGSLHSSQGLGMGPVEESWFA PSLEHPQEENEPSLQSKLQDEANYHLYGSRMDRQTKQQPRQNVAYNREEERRRRVSHDPF AQQRPYENFQNTEGKGTAYSSAASHGNAVHQPSGLTSQPQVLYQNNGLYSSHGFGTRPLD PGTAGPRVWYRPIPSHMPSLHNIPVPETNYLGNTPTMPFSSLPPTDESIKYTIYNSTGIQ IGAYNYMEIGGTSSSLLDSTNTNFKEEPAAKYQAIFDNTTSLTDKHLDPIRENLGKHWKN CARKLGFTQSQIDEIDHDYERDGLKEKVYQMLQKWVMREGIKGATVGKLAQALHQCSRID LLSSLIYVSQN Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 6 Clinical Trial Drugs | + | ||||
| 1 | DNL758 | Drug Info | Phase 2 | Cutaneous lupus erythematosus | [2] | |
| 2 | GSK2982772 | Drug Info | Phase 2 | Plaque psoriasis | [3] | |
| 3 | GSK3145095 | Drug Info | Phase 1/2 | Pancreatic cancer | [4] | |
| 4 | DNL104 | Drug Info | Phase 1 | Alzheimer disease | [5] | |
| 5 | DNL747 | Drug Info | Phase 1 | Alzheimer disease | [6] | |
| 6 | R552 | Drug Info | Phase 1 | Nervous system paraneoplastic or autoimmune disorders | [7] | |
| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | GNE684 | Drug Info | Preclinical | Inflammation | [8] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 14 Inhibitor drugs | + | ||||
| 1 | DNL758 | Drug Info | [9] | |||
| 2 | GSK2982772 | Drug Info | [1], [3] | |||
| 3 | GSK3145095 | Drug Info | [10] | |||
| 4 | DNL104 | Drug Info | [5] | |||
| 5 | DNL747 | Drug Info | [9] | |||
| 6 | R552 | Drug Info | [9] | |||
| 7 | Tricyclic compound 10 | Drug Info | [11] | |||
| 8 | Tricyclic compound 8 | Drug Info | [11] | |||
| 9 | Tricyclic compound 9 | Drug Info | [11] | |||
| 10 | GNE684 | Drug Info | [12] | |||
| 11 | GSK'963 | Drug Info | [13] | |||
| 12 | PK68 | Drug Info | [14] | |||
| 13 | PMID24900635C21 | Drug Info | [15] | |||
| 14 | RIPA-56 | Drug Info | [16] | |||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | ClinicalTrials.gov (NCT04781816) Proof of Concept Study of SAR443122 in Patients With Cutaneous Lupus Erythematosus (CLEan). U.S. National Institutes of Health. | |||||
| REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | ClinicalTrials.gov (NCT03681951) First-time-in-human (FTIH) Study of GSK3145095 Alone and in Combination With Other Anticancer Agents in Adults With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 5 | 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. | |||||
| REF 6 | ClinicalTrials.gov (NCT03757325) Study to Evaluate DNL747 in Subjects With Alzheimer's Disease. U.S. National Institutes of Health. | |||||
| REF 7 | Clinical pipeline report, company report or official report of Rigel. | |||||
| REF 8 | RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases. Cell Death Differ. 2020 Jan;27(1):161-175. | |||||
| REF 9 | Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target. Nat Rev Drug Discov. 2020 Aug;19(8):553-571. | |||||
| REF 10 | 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. | |||||
| REF 11 | 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. | |||||
| REF 12 | Impaired RIPK1 ubiquitination sensitizes mice to TNF toxicity and inflammatory cell death. Cell Death Differ. 2021 Mar;28(3):985-1000. | |||||
| REF 13 | Characterization of GSK'963: a structurally distinct, potent and selective inhibitor of RIP1 kinase. Cell Death Discov. 2015 Jul 27;1:15009. | |||||
| REF 14 | 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. | |||||
| REF 15 | 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. | |||||
| REF 16 | Inhibition of receptor-interacting protein kinase 1 improves experimental non-alcoholic fatty liver disease. J Hepatol. 2020 Apr;72(4):627-635. | |||||
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