Details of the Drug Therapeutic Target (DTT)

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

DTT Name Renal carcinoma antigen NY-REN-64 (IRAK-4)
Synonyms Interleukin-1 receptor-associated kinase 4; IRAK-4
Gene Name IRAK4
DTT Type
Clinical trial target
 [1]
BioChemical Class
Kinase
UniProt ID
IRAK4_HUMAN
TTD ID
T55398
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
EC 2.7.11.1
Sequence
MNKPITPSTYVRCLNVGLIRKLSDFIDPQEGWKKLAVAIKKPSGDDRYNQFHIRRFEALL
QTGKSPTSELLFDWGTTNCTVGDLVDLLIQNEFFAPASLLLPDAVPKTANTLPSKEAITV
QQKQMPFCDKDRTLMTPVQNLEQSYMPPDSSSPENKSLEVSDTRFHSFSFYELKNVTNNF
DERPISVGGNKMGEGGFGVVYKGYVNNTTVAVKKLAAMVDITTEELKQQFDQEIKVMAKC
QHENLVELLGFSSDGDDLCLVYVYMPNGSLLDRLSCLDGTPPLSWHMRCKIAQGAANGIN
FLHENHHIHRDIKSANILLDEAFTAKISDFGLARASEKFAQTVMTSRIVGTTAYMAPEAL
RGEITPKSDIYSFGVVLLEIITGLPAVDEHREPQLLLDIKEEIEDEEKTIEDYIDKKMND
ADSTSVEAMYSVASQCLHEKKNKRPDIKKVQQLLQEMTAS
Function
Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.
KEGG Pathway
MAPK signaling pathway (hsa04010 )
NF-kappa B signaling pathway (hsa04064 )
Toll-like receptor signaling pathway (hsa04620 )
NOD-like receptor signaling pathway (hsa04621 )
Neurotrophin signaling pathway (hsa04722 )
Alcoholic liver disease (hsa04936 )
Pathogenic Escherichia coli infection (hsa05130 )
Salmonella infection (hsa05132 )
Pertussis (hsa05133 )
Yersinia infection (hsa05135 )
Leishmaniasis (hsa05140 )
Chagas disease (hsa05142 )
Toxoplasmosis (hsa05145 )
Tuberculosis (hsa05152 )
Hepatitis B (hsa05161 )
Measles (hsa05162 )
Influenza A (hsa05164 )
Herpes simplex virus 1 infection (hsa05168 )
Epstein-Barr virus infection (hsa05169 )
Human immunodeficiency virus 1 infection (hsa05170 )
Coronavirus disease - COVID-19 (hsa05171 )
Lipid and atherosclerosis (hsa05417 )
Reactome Pathway
Interleukin-1 signaling (R-HSA-446652 )
MyD88 deficiency (TLR2/4) (R-HSA-5602498 )
MyD88 deficiency (TLR5) (R-HSA-5602680 )
IRAK4 deficiency (TLR5) (R-HSA-5603037 )
IRAK4 deficiency (TLR2/4) (R-HSA-5603041 )
TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling (R-HSA-975110 )
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation (R-HSA-975138 )
MyD88 dependent cascade initiated on endosome (R-HSA-975155 )
MyD88 cascade initiated on plasma membrane (R-HSA-975871 )
MyD88 (R-HSA-166058 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
6 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
GS-5718 DMRKU0L Rheumatoid arthritis FA20 Phase 2 [2]
Zabedosertib DMEZGWP Atopic dermatitis EA80 Phase 2 [3]
AZD6793 DM5GRZV Inflammation 1A00-CA43.1 Phase 1 [4]
BAY1834845 DM8V62T Psoriasis vulgaris EA90 Phase 1 [5]
CA-4948 DMWV8C6 Lymphoma 2A80-2A86 Phase 1 [1]
SAR444656 DMIF2OL Atopic dermatitis EA80 Phase 1 [6]
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⏷ Show the Full List of 6 Clinical Trial Drug(s)
21 Patented Agent(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Amidopyrazole derivative 1 DM5X92S N. A. N. A. Patented [7]
Amidopyrazole derivative 2 DMGO9WY N. A. N. A. Patented [7]
Amidopyrazole derivative 3 DMTHS3L N. A. N. A. Patented [7]
Amidopyrazole derivative 4 DMF6N7Z N. A. N. A. Patented [7]
Amidopyrazole derivative 5 DMJ37V2 N. A. N. A. Patented [7]
Amidopyrazole derivative 6 DMJZ1IG N. A. N. A. Patented [7]
Diaminopyridine analog 4 DMPUH4Z N. A. N. A. Patented [7]
Diaminopyridine analog 5 DM5B0F3 N. A. N. A. Patented [7]
Fused benzoheterocycle amide derivative 1 DMKLO2H N. A. N. A. Patented [7]
Fused benzoheterocycle amide derivative 2 DM9NMHS N. A. N. A. Patented [7]
Indazole amide derivative 1 DMKUT6S N. A. N. A. Patented [7]
Indazole amide derivative 2 DMRPT5O N. A. N. A. Patented [7]
Indazoletriazolephenyl derivative 1 DMHJDU6 N. A. N. A. Patented [7]
Indazoletriazolephenyl derivative 2 DMWZLK6 N. A. N. A. Patented [7]
Macrolactam derivative 1 DM0ON7S N. A. N. A. Patented [7]
Macrolactam derivative 2 DME72VA N. A. N. A. Patented [7]
Macrolactam derivative 3 DMFNGUV N. A. N. A. Patented [7]
Macrolactam derivative 4 DM5AXHF N. A. N. A. Patented [7]
Pyrazole N-1 aryl and heteroaryl derivative 1 DMVX7YT N. A. N. A. Patented [7]
Pyrazolopyrimidine and thienopyrimidine amide derivative 1 DM6TB4Z N. A. N. A. Patented [7]
Pyrazolopyrimidine and thienopyrimidine amide derivative 2 DMFUNH4 N. A. N. A. Patented [7]
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⏷ Show the Full List of 21 Patented Agent(s)
8 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
IRAK-1/4 inhibitor DMOQBGP Discovery agent N.A. Investigative [8]
IRAK4 inhibitor 4b DMC80TA Discovery agent N.A. Investigative [9]
IRAK4 inhibitor rac-45 DM1XHNW Discovery agent N.A. Investigative [10]
ND-2110 DMMODRE Discovery agent N.A. Investigative [11]
ND-2158 DMH7GLE Discovery agent N.A. Investigative [11]
PF-05313261 DMOLI1E Inflammation 1A00-CA43.1 Investigative [12]
WO2012007375C1 DMOZATX Discovery agent N.A. Investigative [12]
WO2012007375C7 DMPI2MA Discovery agent N.A. Investigative [12]
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⏷ Show the Full List of 8 Investigative Drug(s)

References

1 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
2 IRAK4 degrader to take on innate immunity. Nat Biotechnol. 2020 Nov;38(11):1221-1223.
3 Oral IRAK4 inhibitor BAY-1834845 prevents acute respiratory distress syndrome. Biomed Pharmacother. 2022 Sep;153:113459.
4 Clinical pipeline report, company report or official report of AstraZeneca
5 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
6 Clinical pipeline report, company report or official report of Sanofi
7 Inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4): a patent review (2012-2015).Expert Opin Ther Pat. 2016 Aug;26(8):917-32.
8 Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4. Bioorg Med Chem Lett. 2006 Jun 1;16(11):2842-5.
9 IRAK-4 inhibitors. Part 1: a series of amides. Bioorg Med Chem Lett. 2008 Jun 1;18(11):3211-4.
10 IRAK-4 inhibitors. Part III: a series of imidazo[1,2-a]pyridines. Bioorg Med Chem Lett. 2008 Jun 15;18(12):3656-60.
11 Recent advances in the discovery of small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders. J Med Chem. 2015 Jan 8;58(1):96-110.
12 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: 2045).