Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Toll-like receptor 4 (TLR4)
• Synonyms: TLR-4; HToll; CD284
• Gene Name: TLR4
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Toll-like receptor
• UniProt ID: TLR4_HUMAN
• TTD ID: T81443
• Sequence:
  MMSASRLAGTLIPAMAFLSCVRPESWEPCVEVVPNITYQCMELNFYKIPDNLPFSTKNLD
  LSFNPLRHLGSYSFFSFPELQVLDLSRCEIQTIEDGAYQSLSHLSTLILTGNPIQSLALG
  AFSGLSSLQKLVAVETNLASLENFPIGHLKTLKELNVAHNLIQSFKLPEYFSNLTNLEHL
  DLSSNKIQSIYCTDLRVLHQMPLLNLSLDLSLNPMNFIQPGAFKEIRLHKLTLRNNFDSL
  NVMKTCIQGLAGLEVHRLVLGEFRNEGNLEKFDKSALEGLCNLTIEEFRLAYLDYYLDDI
  IDLFNCLTNVSSFSLVSVTIERVKDFSYNFGWQHLELVNCKFGQFPTLKLKSLKRLTFTS
  NKGGNAFSEVDLPSLEFLDLSRNGLSFKGCCSQSDFGTTSLKYLDLSFNGVITMSSNFLG
  LEQLEHLDFQHSNLKQMSEFSVFLSLRNLIYLDISHTHTRVAFNGIFNGLSSLEVLKMAG
  NSFQENFLPDIFTELRNLTFLDLSQCQLEQLSPTAFNSLSSLQVLNMSHNNFFSLDTFPY
  KCLNSLQVLDYSLNHIMTSKKQELQHFPSSLAFLNLTQNDFACTCEHQSFLQWIKDQRQL
  LVEVERMECATPSDKQGMPVLSLNITCQMNKTIIGVSVLSVLVVSVVAVLVYKFYFHLML
  LAGCIKYGRGENIYDAFVIYSSQDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAA
  NIIHEGFHKSRKVIVVVSQHFIQSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKVEKTLLR
  QQVELYRLLSRNTYLEWEDSVLGRHIFWRRLRKALLDGKSWNPEGTVGTGCNWQEATSI
• Function: Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific. Both M. tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this protein to stimulate NF-kappa-B expression. In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-). Stimulation of monocytes in vitro with M. tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via TLR2, but also partially via this receptor. Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS).
• KEGG Pathway:
  NF-kappa B signaling pathway (hsa04064)
  HIF-1 signaling pathway (hsa04066)
  Phagosome (hsa04145)
  PI3K-Akt signaling pathway (hsa04151)
  Toll-like receptor signaling pathway (hsa04620)
  Pathogenic Escherichia coli infection (hsa05130)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Leishmaniasis (hsa05140)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Malaria (hsa05144)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Proteoglycans in cancer (hsa05205)
  Inflammatory bowel disease (IBD) (hsa05321)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  Toll Like Receptor 4 (TLR4) Cascade (R-HSA-166016)
  MyD88 (R-HSA-166058)
  MyD88-independent TLR3/TLR4 cascade (R-HSA-166166)
  TRIF-mediated programmed cell death (R-HSA-2562578)
  MyD88 deficiency (TLR2/4) (R-HSA-5602498)
  IRAK4 deficiency (TLR2/4) (R-HSA-5603041)
  Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon (R-HSA-936964)
  IKK complex recruitment mediated by RIP1 (R-HSA-937041)
  TRAF6 mediated induction of TAK1 complex (R-HSA-937072)
  Ligand-dependent caspase activation (R-HSA-140534)

Molecular Interaction Atlas (MIA) of This DTT

9 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MPL-containing Pollinex allergy desensitization vaccine	DMXSDJU	Allergy	4A80-4A85	Preregistration	[1]
Cadi-05	DMPTCYB	Prostate cancer	2C82.0	Phase 3	[2]
ERITORAN	DMKQZ0L	Sepsis	1G40-1G41	Phase 3	[3]
Resatorvid	DMFMWYC	Sepsis	1G40-1G41	Phase 3	[4]
G100	DMKHNXA	Non-hodgkin lymphoma	2B33.5	Phase 2	[5]
CRX-675	DMHDSYF	Hepatitis virus infection	1E50-1E51	Phase 1	[6]
GSK1795091	DMC6QE4	Solid tumour/cancer	2A00-2F9Z	Phase 1	[5]
NI-0101	DM31FOP	Autoimmune diabetes	5A10	Phase 1	[6]
OM-174	DM2THBX	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CS-4771	DMVDLT4	Sepsis	1G40-1G41	Discontinued in Phase 1	[8]
LZ-8	DM679IY	Autoimmune diabetes	5A10	Terminated	[6]

10 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3-Hydroxy-Myristic Acid	DMFJLWO	Discovery agent	N.A.	Investigative	[9]
6-(2-aminophenoxy)benzo[d]isothiazol-3-amine	DMXFRW9	Discovery agent	N.A.	Investigative	[3]
AS04	DMAWJPE	Discovery agent	N.A.	Investigative	[6]
CRX-526	DMW61UK	Discovery agent	N.A.	Investigative	[10]
Fibronectin extra domain A	DMUX702	Discovery agent	N.A.	Investigative	[6]
Lauric Acid	DM9C8KQ	Discovery agent	N.A.	Investigative	[9]
MYRISTIC ACID	DMYX0BL	Discovery agent	N.A.	Investigative	[11]
OM-197-MP-AC	DME8RNV	Solid tumour/cancer	2A00-2F9Z	Investigative	[6]
OM-294-DP	DML5AWQ	Solid tumour/cancer	2A00-2F9Z	Investigative	[6]
TriMixDC	DML3OYH	Melanoma	2C30	Investigative	[12]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Neonatal sepsis	1G41	Whole blood	9.56E-22	1.54	1.84
Prostate cancer	2C82	Prostate	5.26E-01	0.35	0.46
Sepsis with septic shock	1G41	Whole blood	6.50E-34	0.98	1.44
Melanoma	2C82	Skin	2.37E-01	0.46	0.65

References

• [1] Allergy Therapeutics PLC. News Announcement. Allergy Therapeutics. Clinical Trials. Allergy Therapeutics PLC. 11 October 2006.
• [2] Trial Watch: Experimental Toll-like receptor agonists for cancer therapy. Oncoimmunology. 2012 August 1; 1(5): 699-716.
• [3] Small molecule modulators of toll-like receptors. J Med Chem. 2008 Nov 13;51(21):6621-6.
• [4] Clinical pipeline report, company report or official report of Takeda (2009).
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] URL: 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).
• [7] Phase 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.
• [8] Eritoran insight for influenza treatment. SciBX 6(19); doi:10.1038/scibx.2013.453. May 16 2013
• [9] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [10] The 'Ethereal' nature of TLR4 agonism and antagonism in the AGP class of lipid A mimetics. Bioorg Med Chem Lett. 2008 Oct 15;18(20):5350-4.
• [11] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [12] Characterization 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.