AZ1495

AZ1495, a weak base, is a potent orally active interleukin-1 receptor associated kinase 4 (IRAK4) inhibitor. AZ1495 has a favorable physicochemical and kinase selectivity for IRAK4 and IRAK1 with IC 50 values of 0.005 μM and 0.023 μM, respectively. AZ1495 has IRAK4 inhibition with a K d value of 0.0007 μM. AZ1495 can be used for the research of diffuse large B-cell lymphoma (DLBCL) In Vitro AZ1495 (compound 28) (10 μM,1 h) has kinase selectivity for IRAK4 with IC 50 values of 0.005 μM (enzyme assay) and 0.052 μM (cellular assay), respectively. AZ1495 (10 μM,1 h) has kinase inhibition for IRAK4 with an IC 50 value of 0.005 μM and K d value of 0.0007 μM. AZ1495 (0.001-100 μM, 72 h) inhibits NF-κB activation and growth of ABC-DLBCL cell lines in a dosedependent manner. AZ1495 (0-3.3 μM, 14 h) completely inhibits NF-κB signaling and induces cell death at lower concentration in combination with a BTK inhibitor in OCI-LY10 cells. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Viability AssayCell Line: OCI-LY10 and SUDHL2 cells Concentration: 0.001-100 μM Incubation Time: 72 h Result: Inhibited growth of OCI-LY10 cells in a dosedependent manner, whereas SUDHL2, a GCB-cell line was not sensitive and no increased cell killing to IRAK4 inhibitor. Increased the cell death in OCI-LY10 cells upon increasing concentrations of compound 28 and BTK ibrutinib. Western Blot AnalysisCell Line: OCI-LY10 cells Concentration: 0-3.3 μM Incubation Time: 14 h Result: Inhibited IκBα phosphorylation with dose-dependentence in OCI-LY10 cells. Showed induction of apoptosis combination with 10 nM ibrutinib by cleavage of caspase 3 in OCI-LY10 cells. In Vivo AZ1495 (compound 28) (oral, daily, 12.5 mg/kg) leds to tumor regression combination with ibrutinib in an ABC-DLBCL mouse model (OCI-LY10 cells) . AZ1495 (iv., 2 mg/kg and oral, 5mg/kg) is characterized by high clearance (Cl) in rat (75 mL/min/kg) and moderate predictions based on hepatocyte data (Clint 15 μl/min/106 cells, predicted clearance 42 mL/min/kg) with low bioavailability consistent with a high first pass effect . AZ1495 (iv., 1 mg/kg) has low the amount of active renal secretion occurring in the dog . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: CB.17 SCID mice Dosage: 12.5 mg/kg Administration: oral, daily, 12.5 mg/kg Result: Had modest anti-tumor activity as single agents but a combination ofibrutinib led to tumor regression and is well tolerated. Animal Model: rat Dosage: 2 mg/kg, 5mg/kg Administration: iv., 2 mg/kg and oral, 5mg/kg Result: Species Dose (mg/kg) Cl (mL/min/kg) Vss(L/kg) PO halflife (h) IV halflife (h) Fabs (%) F (%) Rat 2，5 75 2.1 2.0 0.8 100 28 Dog 1 29 3.0 - 3.3 - - Animal Model: dog Dosage: 1 mg/kg Administration: iv., 1 mg/kg Result: Species Dose (mg/kg) Cl (mL/min/kg) Vss(L/kg) PO halflife (h) IV halflife (h) Fabs (%) F (%) Rat 2，5 75 2.1 2.0 0.8 100 28 Dog 1 29 3.0 - 3.3 - - Form:Solid IC50& Target:IRAK4 5 nM (IC 50 ) IRAK1 23 nM (IC 50 ) CLK1 50 nM (IC 50 ) CLK2 5 nM (IC 50 ) CLK4 8 nM (IC 50 ) haspin 4 nM (IC 50 )

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