IRAK4-IN-28

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

一种新型有效的选择性 IRAK4 抑制剂，IC50 为 51 nM。

A novel potent, selective IRAK4 inhibitor with IC50 of 51 nM; demonstrates inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro in combination with ibrutinib; shows tumor regression against mutant MYD88L265P DLBCL.

AZ1495 (compound 28) (10 μM,1 h) has kinase selectivity for IRAK4 with IC50 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 IC50 value of 0.005 μM and Kd 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. 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 Analysis Cell 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.

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) inrat (75 mL/min/kg) and moderate predictions based on hepatocyte data (Clint 15μl/min/106 cells, predicted clearance 42 mL/min/kg) with low bioavailability consistent witha high first pass effect.AZ1495 (iv., 1 mg/kg) has low the amount of active renal secretion occurring in the dog. 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.

IRAK4 inhibitor 28

Immunology/Inflammation

IRAK

IRAK

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2196204-23-4

385.512

C21H31N5O2

>98% (HPLC)

10 mM in DMSO

C12=NC=NC(N[C@H]3CC[C@H](N4CCOCC4)CC3)=C1C(C5CCOCC5)=CN2

N-((1r,4r)-4-morpholinocyclohexyl)-5-(tetrahydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

(-20℃)

With Ice Pack

≥ 2 years