Target Information

Target General Infomation
Target ID
T81443
Former ID
TTDC00209
Target Name
Toll-like receptor 4
Gene Name
TLR4
Synonyms
HToll; TLR-4; TLR4
Target Type
Clinical Trial
Disease Autoimmune diabetes [ICD10: E08-E13]
Allergy [ICD9: 995.3; ICD10: T78.4]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Hepatitis virus infection [ICD9: 573.3; ICD10: K75.9]
Melanoma [ICD9: 172; ICD10: C43]
Prostate cancer [ICD9: 185; ICD10: C61]
Septic shock [ICD9: 785.52; ICD10: A41.9]
Sepsis [ICD9: 995.91; ICD10: A40, A41]
Function
Cooperates with ly96 and cd14 to mediate the innate immune response to bacterial lipopolysaccharide (lps). Acts via myd88, tirap and traf6, leading to nf-kappa-b activation, cytokine secretion and the inflammatoryresponse.
BioChemical Class
Toll-like receptor family
Target Validation
T81443
UniProt ID
O00206
Sequence
MMSASRLAGTLIPAMAFLSCVRPESWEPCVEVVPNITYQCMELNFYKIPDNLPFSTKNLD
LSFNPLRHLGSYSFFSFPELQVLDLSRCEIQTIEDGAYQSLSHLSTLILTGNPIQSLALG
AFSGLSSLQKLVAVETNLASLENFPIGHLKTLKELNVAHNLIQSFKLPEYFSNLTNLEHL
DLSSNKIQSIYCTDLRVLHQMPLLNLSLDLSLNPMNFIQPGAFKEIRLHKLTLRNNFDSL
NVMKTCIQGLAGLEVHRLVLGEFRNEGNLEKFDKSALEGLCNLTIEEFRLAYLDYYLDDI
IDLFNCLTNVSSFSLVSVTIERVKDFSYNFGWQHLELVNCKFGQFPTLKLKSLKRLTFTS
NKGGNAFSEVDLPSLEFLDLSRNGLSFKGCCSQSDFGTTSLKYLDLSFNGVITMSSNFLG
LEQLEHLDFQHSNLKQMSEFSVFLSLRNLIYLDISHTHTRVAFNGIFNGLSSLEVLKMAG
NSFQENFLPDIFTELRNLTFLDLSQCQLEQLSPTAFNSLSSLQVLNMSHNNFFSLDTFPY
KCLNSLQVLDYSLNHIMTSKKQELQHFPSSLAFLNLTQNDFACTCEHQSFLQWIKDQRQL
LVEVERMECATPSDKQGMPVLSLNITCQMNKTIIGVSVLSVLVVSVVAVLVYKFYFHLML
LAGCIKYGRGENIYDAFVIYSSQDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAA
NIIHEGFHKSRKVIVVVSQHFIQSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKVEKTLLR
QQVELYRLLSRNTYLEWEDSVLGRHIFWRRLRKALLDGKSWNPEGTVGTGCNWQEATSI
Drugs and Mode of Action
Drug(s) MPL-containing Pollinex allergy desensitization vaccine Drug Info Preregistration Allergy [546900]
Cadi-05 Drug Info Phase 3 Prostate cancer [522525]
ERITORAN Drug Info Phase 3 Septic shock [468097], [521840]
Resatorvid Drug Info Phase 3 Sepsis [522254]
CRX-675 Drug Info Phase 1 Hepatitis virus infection [521583]
NI-0101 Drug Info Phase 1 Autoimmune diabetes [524234]
OM-174 Drug Info Phase 1 Cancer [524222]
CS-4771 Drug Info Discontinued in Phase 1 Sepsis [549092]
LZ-8 Drug Info Terminated Autoimmune diabetes [546038]
Inhibitor 3-Hydroxy-Myristic Acid Drug Info [551393]
6-(2-aminophenoxy)benzo[d]isothiazol-3-amine Drug Info [529731]
CRX-526 Drug Info [529737]
ERITORAN Drug Info [529731]
Lauric Acid Drug Info [551393]
MYRISTIC ACID Drug Info [551374]
Modulator AS04 Drug Info [543474]
CS-4771 Drug Info [551205]
LZ-8 Drug Info [543474]
OM-174 Drug Info [532290]
OM-197-MP-AC Drug Info [543474]
OM-294-DP Drug Info [543474]
Agonist CRX-675 Drug Info [543474]
Antagonist Resatorvid Drug Info [536637], [551717], [551795]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway NF-kappa B signaling pathway
HIF-1 signaling pathway
Phagosome
PI3K-Akt signaling pathway
Toll-like receptor signaling pathway
Pathogenic Escherichia coli infection
Salmonella infection
Pertussis
Legionellosis
Leishmaniasis
Chagas disease (American trypanosomiasis)
Malaria
Toxoplasmosis
Amoebiasis
Tuberculosis
Hepatitis B
Measles
Influenza A
Proteoglycans in cancer
Inflammatory bowel disease (IBD)
Rheumatoid arthritis
NetPath Pathway IL5 Signaling Pathway
IL2 Signaling Pathway
IL4 Signaling Pathway
PANTHER Pathway Toll receptor signaling pathway
Pathway Interaction Database Endogenous TLR signaling
Reactome Ligand-dependent caspase activation
Toll Like Receptor 4 (TLR4) Cascade
Mal cascade initiated on plasma membrane
MyD88-independent TLR3/TLR4 cascade
TRIF-mediated programmed cell death
MyD88 deficiency (TLR2/4)
IRAK4 deficiency (TLR2/4)
Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon
IKK complex recruitment mediated by RIP1
TRAF6 mediated induction of TAK1 complex
WikiPathways Toll-like receptor signaling pathway
Toll-Like Receptors Cascades
Mal cascade initiated on plasma membrane
MyD88-independent cascade
Primary Focal Segmental Glomerulosclerosis FSGS
Spinal Cord Injury
Corticotropin-releasing hormone
Pathogenic Escherichia coli infection
Regulation of toll-like receptor signaling pathway
References
Ref 468097(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4919).
Ref 521583ClinicalTrials.gov (NCT00076037) Safety of and Immune Response to a New HIV Vaccine: HIV CTL MEP. U.S. National Institutes of Health.
Ref 521840ClinicalTrials.gov (NCT00334828) ACCESS: A Controlled Comparison of Eritoran Tetrasodium and Placebo in Patients With Severe Sepsis. U.S. National Institutes of Health.
Ref 522254ClinicalTrials.gov (NCT00633477) Efficacy and Safety of Resatorvid in Patients With Sepsis-induced Cardiovascular and Respiratory Failure. U.S. National Institutes of Health.
Ref 522525ClinicalTrials.gov (NCT00810849) A Trial of Adjunctive Prednisolone and Mycobacterium w Immunotherapy in Tuberculous Pericarditis. U.S. National Institutes of Health.
Ref 524222ClinicalTrials.gov (NCT01800812) Effects of OM-174 in Adult Patients With Solid Tumors. U.S. National Institutes of Health.
Ref 524234ClinicalTrials.gov (NCT01808469) First in Human Study of an Anti-Toll-like Receptor 4 (TLR4) Monoclonal Antibody (NI-0101) in Adult Healthy Volunteers. U.S. National Institutes of Health.
Ref 546038Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006001)
Ref 546900Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010983)
Ref 549092Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800032166)
Ref 529731J Med Chem. 2008 Nov 13;51(21):6621-6. Epub 2008 Oct 2.Small molecule modulators of toll-like receptors.
Ref 529737Bioorg Med Chem Lett. 2008 Oct 15;18(20):5350-4. Epub 2008 Sep 19.The 'Ethereal' nature of TLR4 agonism and antagonism in the AGP class of lipid A mimetics.
Ref 532273Characterization of CD8+ T-cell responses in the peripheral blood and skin injection sites of melanoma patients treated with mRNA electroporated autologous dendritic cells (TriMixDC-MEL). Biomed Res Int. 2013;2013:976383.
Ref 532290Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors. BMC Cancer. 2013 Apr 2;13:172.
Ref 536637TAK-242 selectively suppresses Toll-like receptor 4-signaling mediated by the intracellular domain. Eur J Pharmacol. 2008 Apr 14;584(1):40-8. Epub 2008 Feb 5.
Ref 543474(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1754).
Ref 544251Trial Watch: Experimental Toll-like receptor agonists for cancer therapy. Oncoimmunology. 2012 August 1; 1(5): 699-716.
Ref 550003Allergy Therapeutics PLC. News Announcement. Allergy Therapeutics. Clinical Trials. Allergy Therapeutics PLC. 11 October 2006.
Ref 551205Eritoran insight for influenza treatment. SciBX 6(19); doi:10.1038/scibx.2013.453. May 16 2013
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 551717Clinical pipeline report, company report or official report of Takeda (2009).
Ref 551795THE NOVEL SELECTIVE TOLL-LIKE RECEPTOR 4 SIGNAL TRANSDUCTION INHIBITOR TAK-242 PREVENTS ENDOTOXAEMIA IN CONSCIOUS GUINEA-PIGS. Clinical and Experimental Pharmacology and Physiology Volume 36, Issue 5-6, pages 589-593, May/June 2009

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