IRAK4
Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that functions as a key mediator in Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways[1][2]. Mechanistically, IRAK4 initiates myddosome formation by recruiting and activating IRAK1, facilitating downstream NF-κB and MAPK signaling[2][3]. Compared with other IRAK family members, IRAK4 possesses both kinase activity and scaffolding functions, with its scaffold role being essential for myddosome assembly independent of catalytic activity[2][3]. Dysregulation or overexpression of IRAK4 contributes to inflammatory, autoimmune, and oncogenic processes, including rheumatoid arthritis, myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML)[1][4][5]. In MDS and AML, long isoforms of IRAK4 (IRAK4-L) produced by spliceosome mutations such as SF3B1 or U2AF1 retain maximal functional domains, driving constitutive NF-κB activation and sustaining leukemic stem cell function[5][6][7]. Selective IRAK4 inhibitors, including DW18134, CA-4948, PF-06650833, and KME-0584, have demonstrated efficacy in preclinical models by reducing proinflammatory cytokines and suppressing leukemic progenitor proliferation[8][9][10]. Dual inhibition of IRAK4 and IRAK1 enhances therapeutic outcomes, as IRAK1 compensatory activation can limit the efficacy of IRAK4-selective agents[9]. Mechanistic studies also highlight that IRAK4 degraders, which eliminate both scaffolding and kinase functions, achieve broader suppression of TLR/IL-1R-induced NF-κB and p38 signaling compared with kinase inhibition alone[3].
References:
- [1]. Singer JW, et al. Inhibition of interleukin-1 receptor-associated kinase 1 (IRAK1) as a therapeutic strategy. Oncotarget. 2018 Sep 7;9(70):33416-33439. [Content Brief]
- [2]. Feng Y, et al. Emerging interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors or degraders as therapeutic agents for autoimmune diseases and cancer. Acta Pharm Sin B. 2024 Dec;14(12):5091-5105. [Content Brief]
- [3]. De Nardo D, et al. Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a dual role in myddosome formation and Toll-like receptor signaling. J Biol Chem. 2018 Sep 28;293(39):15195-15207. [Content Brief]
- [4]. Huang Y, et al. A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease. Molecules. 2024 Apr 16;29(8):1803. [Content Brief]
- [5]. Yoon SB, et al. A novel IRAK4/PIM1 inhibitor ameliorates rheumatoid arthritis and lymphoid malignancy by blocking the TLR/MYD88-mediated NF-κB pathway. Acta Pharm Sin B. 2023 Mar;13(3):1093-1109. [Content Brief]
- [6]. Rosenbaum JS, et al. Inhibition of both IRAK1 and IRAK4 is required for complete suppression of NF-Kb signaling across multiple receptor-mediated pathways in MDS and AML. Blood. 2022;140(Suppl 1):5949.
- [7]. Rosenbaum JS, et al. Kme-0584, a highly potent IRAK1/IRAK4/panFLT3 inhibitor, is a promising clinical candidate for hypomethylating agent plus venetoclax resistant AML/MDS patients. Blood. 2023;142(Suppl 1):4152.
- [8]. Choudhary SA, et al. A small molecule potent IRAK4 inhibitor abrogates lipopolysaccharide-induced macrophage inflammation in-vitro and in-vivo. Eur J Pharmacol. 2023 Apr 5;944:175593. [Content Brief]
- [9]. Hao X, et al. Electromagnetic Functional Properties of Flexible Picosecond Laser-Induced Graphene Films Modified with Silver Nanoparticles. ACS Appl Mater Interfaces. 2026 May 27;18(20):28957-28968. [Content Brief]
- [10]. Choudhary GS, et al. SF3B1 mutations induce oncogenic IRAK4 isoforms and activate targetable innate immune pathways in MDS and AML. Blood. 2019;134(Suppl 1):4224.
- [11]. Skouras SM, et al. Selective IRAK4 degradation, not kinase inhibition, blocks TLR-activated NF-Kb and p38 signaling leading to broad cytokine inhibition. J Immunol. 2022;208(1 Suppl):111.13.
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IRAK4 Related Products (95)
Related Products (95)
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PROTAC IRAK4 degrader-2
0 ImagesCat. No.: HY-135382CAS No.: 2374122-27-5PROTAC IRAK4 degrader-2 is a PROTAC degrader targeting IRAK4. PROTAC IRAK4 degrader-2 induces proteasome-dependent degradation of IRAK4 by recruiting the VHL E3 ligase. PROTAC IRAK4 degrader-2 inhibits multiple cytokines in peripheral blood mononuclear cells. PROTAC IRAK4 degrader-2 can be used in the research of autoimmune diseases, inflammatory diseases and neoplastic diseases.
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KTX-612
0 ImagesCat. No.: HY-148277CAS No.: 2573298-14-1
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AF-45
0 ImagesCat. No.: HY-162641AF-45 inhibits IRAK4 and IRAK1, with IC50s of 128 nM and 1765 nM. AF-45 inhibits the release of IL-6 and TNF-α in macrophages, with IC50s of 0.53-1.54 μM and 0.6-2.75 μM. AF-45 is also an inhibitor for NF-κB/MAPK signaling pathway. AF-45 exhibits anti-inflammatory activities against DSS-induced ulcerative colitis and Lipopolysaccharide (HY-D1056)-induced acute lung injury in mouse model. AF-45 exhibits good pharmacokinetic characteristics in rat models.
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BIO-8169
0 ImagesCat. No.: HY-158374CAS No.: 2792153-06-9BIO-8169 is a selective inhibitor for interleukin receptor-associated kinase 4 (IRAK 4), with an IC50 of 0.23 nM. BIO-8169 exhibits good pharmacokinetic character, reduces the production of pro-inflammatory cytokines, and attenuates the autoimmune encephalomyelitis in EAE mice model. BIO-8169 exhibits good blood brain penetrant with a rat Kpu,u of 0.7.
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PROTAC IRAK3 degrader-1
0 ImagesCat. No.: HY-142662CAS No.: 2712600-00-3
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BMS-986126
0 ImagesCat. No.: HY-124995CAS No.: 1610017-20-3BMS-986126 is a potent, selective, and orally active IRAK4 inhibitor (IC50 = 5.3 nM). BMS-986126 broadly inhibits MyD88-dependent signaling pathways. BMS-986126 demonstrates robust activity in the MRL/lpr and NZB/NZW murine models of lupus, inhibiting multiple pathogenic responses. BMS-986126 can be used for autoimmune diseases research, such as lupus erythematosus (SLE).
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KTX-497
0 ImagesCat. No.: HY-148276CAS No.: 2432993-46-7
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KTX-955
0 ImagesCat. No.: HY-148275CAS No.: 2573302-50-6
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IRAK4-IN-35
0 ImagesCat. No.: HY-187692CAS No.: 3112339-39-3IRAK4-IN-35 is an orally active IRAK4 inhibitor with an IRAK4 IC50 of 9.88 nM. IRAK4-IN-35 also inhibits JAK3, EGFR, CDK2 with IC50 values of 6.72 nM, 32.35 nM, and 39.08 nM, respectively. IRAK4-IN-35 inhibits the production of proinflammatory cytokines, blocks inflammatory signaling pathways, and reduces serum TNF-α levels and spleen index in mouse models of acute inflammation. IRAK4-IN-35 decreases the disease activity index, paw swelling degree, and spleen index in a collagen-induced arthritis mouse model. IRAK4-IN-35 can be used for the research of rheumatoid arthritis.
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IRAK4-IN-15
0 ImagesCat. No.: HY-146113CAS No.: 2667681-85-6IRAK4-IN-15 (compound 35) is a potent and selective IRAK4 inhibitor with an IC50 of 0.002 µM. IRAK4-IN-15 shows good human PK predictions with low intrinsic clearance. IRAK4-IN-15 shows great synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with Acalabrutinib. .
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IRAK4-IN-30
0 ImagesCat. No.: HY-172372CAS No.: 2967595-45-3IRAK4-IN-30 (Compound I) is the inhibitor for IRAK4 with IC50 of 0.6 nM.
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IRAK4-IN-17
0 ImagesCat. No.: HY-150594CAS No.: 2183503-33-3IRAK4-IN-17 (Compound 5) is a potent IRAK4 inhibitor with the IC50 of 1.3 nM. IRAK4-IN-17 can be used in large B-cell lymphoma (DLBCL) research.
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IRAK4-IN-11
0 ImagesCat. No.: HY-146072CAS No.: 3032742-74-5IRAK4-IN-11 (compound 6) is a potent IRAK4 inhibitor with an IC50 of 0.008 µM. IRAK4-IN-11 shows cell pIRAK4 potencies with an IC50 of 0.19 µM.
