AZ1495，一种弱碱，是一种有效的白细胞介素-1 受体相关激酶 4(IRAK4)抑制剂，具有口服活性。AZ1495 对 IRAK4 和 IRAK1 具有良好的理化和激酶选择性，其IC50值分别为 0.005 μM 和 0.023 μM。AZ1495 具有 IRAK4 抑制作用，Kd值为 0.0007 μM。AZ1495 可用于弥漫大 B 细胞淋巴瘤 (DLBCL) 的研究。
| 生物活性 | 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 forIRAK4andIRAK1withIC50values of 0.005 μM and 0.023 μM, respectively. AZ1495 hasIRAK4inhibition with aKdvalue of 0.0007 μM. AZ1495 can be used for the research of diffuse large B-cell lymphoma (DLBCL)[1]. |
| IC50& Target[1] | IRAK4 5 nM (IC50) | IRAK1 23 nM (IC50) | CLK1 50 nM (IC50) | CLK2 5 nM (IC50) | CLK4 8 nM (IC50) | haspin 4 nM (IC50) |
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体外研究
(In Vitro) | AZ1495 (compound 28) (10 μM,1 h) has kinase selectivity for IRAK4 with IC50values of 0.005 μM (enzyme assay) and 0.052 μM (cellular assay), respectively[1].
AZ1495 (10 μM,1 h) has kinase inhibition for IRAK4 with an IC50value of 0.005 μM and Kdvalue of 0.0007 μM[1].
AZ1495 (0.001-100 μM, 72 h) inhibits NF-κB activation and growth of ABC-DLBCL cell lines in a dosedependent manner[1].
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[1].
Cell Viability Assay[1] | Cell 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[1] | 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. |
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体内研究
(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)[1].
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[1].
AZ1495 (iv., 1 mg/kg) has low the amount of active renal secretion occurring in the dog[1].
| Animal Model: | CB.17 SCID mice[1] | | 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[1] | | 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 | - | - | |
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| Animal Model: | dog[1] | | 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 | - | - | |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | | Powder | -20°C | 3 years | | 4°C | 2 years | | In solvent | -80°C | 6 months | | -20°C | 1 month |
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| 溶解性数据 | In Vitro: DMSO : 10 mg/mL(25.94 mM;Need ultrasonic) 配制储备液 | 1 mM | 2.5940 mL | 12.9702 mL | 25.9403 mL | | 5 mM | 0.5188 mL | 2.5940 mL | 5.1881 mL | | 10 mM | 0.2594 mL | 1.2970 mL | 2.5940 mL |
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储备液的保存方式和期限：-80℃, 6 months; -20℃, 1 month。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。 In Vivo: 请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方式配制澄清的储备液，再依次添加助溶剂： ——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用；
以下溶剂前显示的百
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此方案可获得 ≥ 1 mg/mL (2.59 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 10.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。 2. 请依序添加每种溶剂： 10% DMSO 90% (20%SBE-β-CDin saline) Solubility: ≥ 1 mg/mL (2.59 mM); Clear solution
此方案可获得 ≥ 1 mg/mL (2.59 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 10.0 mg/mL 的澄清 DMSO 储备液加到 900 μL20% 的 SBE-β-CD 生理盐水水溶液中，混合均匀。 3. 请依序添加每种溶剂： 10% DMSO 90%corn oil Solubility: ≥ 1 mg/mL (2.59 mM); Clear solution
此方案可获得 ≥ 1 mg/mL (2.59 mM，饱和度未知) 的澄清溶液，此方案不适用于实验周期在半个月以上的实验。 以 1 mL 工作液为例，取 100 μL 10.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。 *以上所有助溶剂都可在本网站选购。
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