Target Information
Target General Information | Top | |||||
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Target ID |
T55398
(Former ID: TTDR00045)
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Target Name |
Renal carcinoma antigen NY-REN-64 (IRAK-4)
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Synonyms |
Interleukin-1 receptor-associated kinase 4; IRAK-4
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Gene Name |
IRAK4
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Lymphoma [ICD-11: 2A80-2A86] | |||||
2 | Psoriasis [ICD-11: EA90] | |||||
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.
Click to Show/Hide
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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 |
MNKPITPSTYVRCLNVGLIRKLSDFIDPQEGWKKLAVAIKKPSGDDRYNQFHIRRFEALL
QTGKSPTSELLFDWGTTNCTVGDLVDLLIQNEFFAPASLLLPDAVPKTANTLPSKEAITV QQKQMPFCDKDRTLMTPVQNLEQSYMPPDSSSPENKSLEVSDTRFHSFSFYELKNVTNNF DERPISVGGNKMGEGGFGVVYKGYVNNTTVAVKKLAAMVDITTEELKQQFDQEIKVMAKC QHENLVELLGFSSDGDDLCLVYVYMPNGSLLDRLSCLDGTPPLSWHMRCKIAQGAANGIN FLHENHHIHRDIKSANILLDEAFTAKISDFGLARASEKFAQTVMTSRIVGTTAYMAPEAL RGEITPKSDIYSFGVVLLEIITGLPAVDEHREPQLLLDIKEEIEDEEKTIEDYIDKKMND ADSTSVEAMYSVASQCLHEKKNKRPDIKKVQQLLQEMTAS Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T62ERY |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
1 | BAY1834845 | Drug Info | Phase 1 | Psoriasis vulgaris | [2] | |
2 | CA-4948 | Drug Info | Phase 1 | Lymphoma | [1] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 31 Inhibitor drugs | + | ||||
1 | BAY1834845 | Drug Info | [2] | |||
2 | CA-4948 | Drug Info | [1] | |||
3 | Amidopyrazole derivative 1 | Drug Info | [3] | |||
4 | Amidopyrazole derivative 2 | Drug Info | [3] | |||
5 | Amidopyrazole derivative 3 | Drug Info | [3] | |||
6 | Amidopyrazole derivative 4 | Drug Info | [3] | |||
7 | Amidopyrazole derivative 5 | Drug Info | [3] | |||
8 | Amidopyrazole derivative 6 | Drug Info | [3] | |||
9 | Diaminopyridine analog 4 | Drug Info | [3] | |||
10 | Diaminopyridine analog 5 | Drug Info | [3] | |||
11 | Fused benzoheterocycle amide derivative 1 | Drug Info | [3] | |||
12 | Fused benzoheterocycle amide derivative 2 | Drug Info | [3] | |||
13 | Indazole amide derivative 1 | Drug Info | [3] | |||
14 | Indazole amide derivative 2 | Drug Info | [3] | |||
15 | Indazoletriazolephenyl derivative 1 | Drug Info | [3] | |||
16 | Indazoletriazolephenyl derivative 2 | Drug Info | [3] | |||
17 | Macrolactam derivative 1 | Drug Info | [3] | |||
18 | Macrolactam derivative 2 | Drug Info | [3] | |||
19 | Macrolactam derivative 3 | Drug Info | [3] | |||
20 | Macrolactam derivative 4 | Drug Info | [3] | |||
21 | Pyrazole N-1 aryl and heteroaryl derivative 1 | Drug Info | [3] | |||
22 | Pyrazolopyrimidine and thienopyrimidine amide derivative 1 | Drug Info | [3] | |||
23 | Pyrazolopyrimidine and thienopyrimidine amide derivative 2 | Drug Info | [3] | |||
24 | IRAK-1/4 inhibitor | Drug Info | [4] | |||
25 | IRAK4 inhibitor 4b | Drug Info | [5] | |||
26 | IRAK4 inhibitor rac-45 | Drug Info | [6] | |||
27 | ND-2110 | Drug Info | [7] | |||
28 | ND-2158 | Drug Info | [7] | |||
29 | PF-05313261 | Drug Info | [8] | |||
30 | WO2012007375C1 | Drug Info | [8] | |||
31 | WO2012007375C7 | Drug Info | [8] |
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 Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs | ||||||
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 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 3 | Inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4): a patent review (2012-2015).Expert Opin Ther Pat. 2016 Aug;26(8):917-32. | |||||
REF 4 | Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4. Bioorg Med Chem Lett. 2006 Jun 1;16(11):2842-5. | |||||
REF 5 | IRAK-4 inhibitors. Part 1: a series of amides. Bioorg Med Chem Lett. 2008 Jun 1;18(11):3211-4. | |||||
REF 6 | IRAK-4 inhibitors. Part III: a series of imidazo[1,2-a]pyridines. Bioorg Med Chem Lett. 2008 Jun 15;18(12):3656-60. | |||||
REF 7 | 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. | |||||
REF 8 | 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). |
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