Interleukin-1 receptor-associated kinase (IRAK) is first described as a signal transducer for the proinflammatory cytokine IL-1 and is later implicated in signal transduction of other members of the Toll-like receptor (TLR)/IL-1R family. Four different IRAK-like molecules have been identified: two active kinases, IRAK-1 and IRAK-4, and two inactive kinases, IRAK-2 and IRAK-M. All IRAKs mediate activation of NF-κB and MAPK pathways. IRAKs are protein kinases involved in signalling innate immune responses from TLRs. After TLR-4 and TLR-2 recognize pathogen-associated molecular patterns, such as LPS and peptidoglycan, all IRAK members form multimeric receptor complexes.
IRAKs are essential signaling intermediates in the TLR/IL-1R pathway to both IKK and MAPKs activation. These two pathways are central to the activation of several transcription factors, including NF-κB and AP-1, which contribute to the establishment of an immune response.
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Development of a Scalable Synthesis for the Potent Kinase Inhibitor BMS-986236.
CA-4948 (AU-4948) is a novel potent, selective, orally bioavailable IRAK4 inhibitor; shows in vivo activity in TLR4-induced cytokine release model, exhibits dose-dependent efficacy in ABC-DLBCL MYD88-L265P xenograft tumor models; a therapeutic agent for hematological cancers with dysregulated TLR/MYD88/IRAK4 signaling, induces tumor regression in an ABC-DLBCL xenograft model combined with Venetoclax.
HG-12-6 is a small-molecule inhibitor that bind preferentially to unphosphorylated IRAK4 with IC50 of 165.1 nM, displays 15-fold selectivity over phosphorylated IRAK4 (IC50=2876 nM); binds as type II inhibitor with IRAK4 in a “DFG-out” conformation.
PF-06650833 (PF06650833) is a potent and selective IRAK4 inhibitor with IC50 of 0.2 nM; has IC50 of 2 nM in the PBMC assay as well as in a human whole blood assay; shows excellent kinase selectivity in a panel of 278 kinases; significantly inhibits LPS-induced TNFα in a dose dependent manner in rats model (0.3-30 mg/kg); has favorable in vitro and in vivo ADME profiles and orally active.
PF-06426779 (PF06426779) is a potent, selective IRAK4 inhibitor with IC50 of 1 nM against full-length IRAK4 kinase and cell-based IC50 of 12 nM; displays excellent selectivity against the human kinome, and >100-fold selectivity for IRAK4 over IRAK1.
IRAK-1-4 Inhibitor I is a potent, dual inhibitor of IRAK4 and IRAK1 with IC50 of 0.2 uM and 0.3 uM, respectively; displays IC50 of >10 uM against a panel of 27 other kinases, including the most closely homologous (outside of the IRAK family) Lck and pp60SRC; eliminates the LPS-induced increases in Bcl10, NF-κB, and IL-8 in human intestinal epithelial cells.
A potent, selective, orally bioavailable IRAK4 inhibitor with IC50 of 7 nM; inhibits R848 (TLR7 agonist) stimulated cytokine release in hPBMC with IC50 of 300 nM; exhibits excellent pharmacokinetic profile and kinase selectivity (99%); demonstrates activity in vivo via oral dosing in TLR7 driven model of inflammation.
IRAK inhibitor 1
IRAK inhibitor 1 is a potent IRAK-4 inhibitor with IC50 of 216 nM, shows little to no activity against JNK-1 and JNK-2 with IC50 of 3.801 uM and >10 uM, respectively.
A potent, selective, orally bioavailable IRAK-4 inhibitor that potently inhibits human and rat IRAK-4 activity with subnanomolar order, >30-fold selectivity over IRAK-1; inhibited IL-1β- or TLR ligand lipopolysaccharide (LPS)-induced IL-6 production in human lung alveolar epithelial cells, fibroblast-like synoviocytes, and peripheral blood mononuclear cells; significantly reduces urinary protein excretion and preventd the development of glomerulosclerosis and interstitial fibrosis without affecting the blood pressure in mice model of chronic kidney disease.
A potent, selective IRAK4 inhibitor with IC50 of 1.3 nM, 200-fold selectivity over IRAK1 (IC50=290 nM); exhibits low nM potency in LPS- and R848-induced cytokine assays (IC50=18 nM) in human PBMCs; inhibits LPS-induced TNFα in an in vivo murine model.
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