PK68 是一种高效、特异性的受体相互作用激酶 1 (RIPK1) 的 II 型抑制剂，具有口服活性。其IC50值约 90 nM，可抑制 RIPK1 依赖性坏死。PK68 对 TNF 诱导的全身炎症反应综合征有较强的改善作用，可用于炎症紊乱和肿瘤转移的研究。
| 生物活性 | PK68 is a potent orally active and specifical type II inhibitor ofreceptor-interacting kinase 1 (RIPK1)with anIC50of ~90 nM, displays inhibition of RIPK1-dependentnecroptosis. PK68 powerfully ameliorates TNF-induced systemic inflammatory response syndrome, and can be used for the research of inflammatory disorders andcancermetastasis[1]. |
| IC50& Target | RIPK1 90 nM (IC50) | RIPK1 23 nM (EC50) |
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体外研究
(In Vitro) | PK68 has highly potent inhibition of TNF-induced necroptosis with EC50values of 23 nM and 13 nM in human and mouse cells, respectively[1].
PK68 is a highly selective inhibitor of RIPK1 kinase activity with IC50value of 90 nM[1].
PK68 (100 nM, 1 h) blocks necroptosis through the suppression of RIPK3 function or signaling upstream of RIPK3 activation[1].
Cell Viability Assay[1] | Cell Line: | Bone marrow-derived macrophages, NIH3T3-RIPK3 cells | | Concentration: | 100 nM | | Incubation Time: | 1 h | | Result: | PK68 block cellular activation of RIPK1, RIPK3, and MLKL upon necroptotic stimuli.
PK68 inhibit TNF-induced necroptosis but not RIPK3 dimerization-induced cell death in NIH3T3-RIPK3 cells. |
Western Blot Analysis[1] | Cell Line: | HT-29 cells | | Concentration: | 100 nM | | Incubation Time: | 1 h | | Result: | Completely abolished phosphorylation of RIPK1, RIPK3, and MLKL. |
Immunofluorescence[1] | Cell Line: | HT-29 cells | | Concentration: | 100 nM | | Incubation Time: | 1 h | | Result: | Prevented generation of RIPK3 puncta. |
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体内研究
(In Vivo) | PK68 (5 mg/kg, 25 mg/kg; oral gavage; daily; for 7 days) or (2 mg/kg, i.v.; 10 mg/kg, p.o.; for 14 days) exhibits a favorable pharmacokinetic profile and no obvious toxicity in mice[1].
PK68 (1 mg/kg, i.p.) ameliorates TNF-induced systemic inflammatory response syndrome[1].
PK68 (5 mg/kg, i.v.) inhibits RIPK1 that results in attenuated tumor cell transmigration across the endothelial barrier and preventive suppression of tumor metastasis[1].
| Animal Model: | C57BL/6 mice[1] | | Dosage: | 5 mg/kg, 25 mg/kg | | Administration: | 5 mg/kg, 25 mg/kg; oral gavage; daily; for 7 days | | Result: | Exhibited favorable pharmacokinetic profiles and no obvious toxicity in mice treated with a 14-day course at a dose of 25 mg/kg. |
| Animal Model: | C57BL/6 mice[1] | | Dosage: | 2 mg/kg, 10 mg/kg | | Administration: | 2 mg/kg, i.v.; 10 mg/kg, p.o; for 14 days | | Result: | | PO (Gavage) | IV (Bolus) | | Tmax(hr) | 0.5 | | | Cmax(ng/mL) | 2423 | | | AUC0-24(ng/mLohr) | 4821 | 1588 | | AUCINF (ng/mLohr) | 4897 | 1590 | | t1/2(hr) | 1.3 | 1.0 | | MRT (hr) | 1.8 | 0.8 | | CL (mL/hr/kg) | | 1258 | | CL (mL/min/kg) | | 21 | | Vss (mL/kg) | | 1009 | | Vss (L/kg) | | 1.0 | | F(%) | 61 | | |
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| Animal Model: | C57BL/6 mice[1] | | Dosage: | 1 mg/kg | | Administration: | 1 mg/kg, i.p. | | Result: | Provided effective protection against TNFα-induced lethal shock. |
| Animal Model: | C57BL/6 mice[1] | | Dosage: | 5 mg/kg | | Administration: | 5 mg/kg, i.v. | | Result: | Significantly reduced the number of pulmonary metastasis nodules, decreased lung metastasis, decreased number of RFP-LL/2 cells, attenuated transmigration of RFP-LL/2 cells through the endothelial cell monolayer and had no obvious influence on the proliferation rate and invasion ability of B16-F10 or RFP-LL/2 cells without the endothelial cell monolayer in vitro. |
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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 : 30 mg/mL(70.67 mM;Need ultrasonic) 配制储备液 | 1 mM | 2.3556 mL | 11.7780 mL | 23.5560 mL | | 5 mM | 0.4711 mL | 2.3556 mL | 4.7112 mL | | 10 mM | 0.2356 mL | 1.1778 mL | 2.3556 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；
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此方案可获得 ≥ 3 mg/mL (7.07 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 30.0 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。 2. 请依序添加每种溶剂： 10% DMSO 40%PEG300 5%Tween-80 45% saline Solubility: ≥ 2.08 mg/mL (4.90 mM); Clear solution
此方案可获得 ≥ 2.08 mg/mL (4.90 mM，饱和度未知) 的澄清溶液。 以 1 mL 工作液为例，取 100 μL 20.8 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。 3. 请依序添加每种溶剂： 10% DMSO 90%corn oil Solubility: ≥ 2.08 mg/mL (4.90 mM); Clear solution
此方案可获得 ≥ 2.08 mg/mL (4.90 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 20.8 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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