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PK68 is a novel, potent and selective type II inhibitor of receptor-interacting kinase 1 (RIPK1) with an IC50 of ~90 nM, exhibiting inhibition of RIPK1-dependent necroptosis. PK68 significantly ameliorates TNF-induced systemic inflammatory response syndrome, and with great potential for use in the treatment of inflammatory disorders and cancer metastasis.
| ln Vitro |
PK68 exhibits a potent inhibitory impact on TNF-induced necroptosis, as demonstrated by its EC50 values of 23 nM in human cells and 13 nM in mouse cells, respectively [1]. With an IC50 value of 90 nM, PK68 is a highly selective inhibitor of RIPK1 kinase activity[1]. Necroptosis is prevented by PK68 (100 nM, 1 hour), which either activates RIPK3's upstream signaling or inhibits its activity [1].
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| ln Vivo |
Good pharmacokinetic qualities, kinetic features, and no evident toxicity were demonstrated in mice by PK68 (5 mg/kg, 25 mg/kg; oral gavage; daily; for 7 days) or (2 mg/kg, intravenous; 10 mg/kg, oral; for 14 days) [1]. TNF-induced systemic inflammatory response syndrome can be ameliorated with an intraperitoneal injection of PK68 (1 mg/kg) [1]. By inhibiting RIPK1, PK68 (5 mg/kg, intravenous injection) reduces tumor cell migration across the endothelium barrier and suppresses tumor metastasis before it occurs [1].
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| Cell Assay |
Cell viability assay [1]
Cell Types: bone marrow-derived macrophages, NIH3T3-RIPK3 Cell Tested Concentrations: 100 nM Incubation Duration: 1 hour Experimental Results: PK68 blocks the cellular activation of RIPK1, RIPK3 and MLKL under necroptosis stimulation. PK68 inhibits TNF-induced necroptosis but not RIPK3 dimerization-induced cell death in NIH3T3-RIPK3 cells. Western Blot Analysis[1] Cell Types: HT-29 Cell Tested Concentrations: 100 nM Incubation Duration: 1 hour Experimental Results: Complete abrogation of phosphorylation of RIPK1, RIPK3 and MLKL. Immunofluorescence[1] Cell Types: HT-29 Cell Tested Concentrations: 100 nM Incubation Duration: 1 hour Experimental Results: Prevents the generation of RIPK3 spots. |
| Animal Protocol |
Animal/Disease Models: C57BL/6 mice[1]
Doses: 5 mg/kg, 25 mg/kg Route of Administration: 5 mg/kg, 25 mg/kg; po (oral gavage); daily; 7-day Experimental Results: at 25 mg /kg dose and a 14-day course of treatment in mice demonstrated good pharmacokinetic/PK/PK characteristics without obvious toxicity. Animal/Disease Models: C57BL/6 mice[1] Doses: 2 mg/kg, 10 mg/kg Route of Administration: 2 mg/kg, intravenous (iv) (iv)injection; 10 mg/kg, oral administration; continued for 14 days Experimental Results: PO (gavage ) IV (bolus injection) Tmax (hr) 0.5 Cmax (ng/mL) 2423 AUC0-24 (ng/mL·hr) 4821 1588 AUCINF (ng/mL·hr) 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 Animal/Disease Models: C57BL/6 mice [ 1] Doses: 1 mg/kg Route of Administration: 1 mg/kg, intraperitoneal (ip) injection Experimental Results: Provides effective protection against TNFα-induced lethal shock. Animal/Disease Models: C57BL/6 mice [1] Doses: 5 mg/kg Route of Administration: 5 mg/kg, intravenous (iv) (iv)injection Experimental Results: The number of lung metastasis nodules was signif |
| References |
| Molecular Formula |
C22H24N4O3S
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|---|---|
| Molecular Weight |
424.5160
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| Exact Mass |
424.156
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| CAS # |
2173556-69-7
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| PubChem CID |
134203923
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
30
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| Complexity |
615
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C(N([H])C(C([H])([H])[H])=O)=NC2C([H])=C([H])C(=C([H])C1=2)C1C([H])=NC(C([H])([H])[H])=C(C=1[H])N([H])C(=O)OC1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H]
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| InChi Key |
DRCNWQYEKZTTEW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H24N4O3S/c1-13-19(26-22(28)29-17-6-4-3-5-7-17)10-16(12-23-13)15-8-9-18-20(11-15)30-21(25-18)24-14(2)27/h8-12,17H,3-7H2,1-2H3,(H,26,28)(H,24,25,27)
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| Chemical Name |
cyclohexyl (5-(2-acetamidobenzo[d]thiazol-6-yl)-2-methylpyridin-3-yl)carbamate
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| Synonyms |
PK68 PK-68 PK 68
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~30 mg/mL (~70.67 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (7.07 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.90 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.90 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 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 |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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