PK68

PK68 is a potent orally active and specifical type II inhibitor of receptor-interacting kinase 1 (RIPK1) with an IC 50 of ~90 nM, displays inhibition of RIPK1-dependent necroptosis . PK68 powerfully ameliorates TNF-induced systemic inflammatory response syndrome, and can be used for the research of inflammatory disorders and cancer metastasis In Vitro PK68 has highly potent inhibition of TNF-induced necroptosis with EC 50 values of 23 nM and 13 nM in human and mouse cells, respectively. PK68 is a highly selective inhibitor of RIPK1 kinase activity with IC 50 value of 90 nM. PK68 (100 nM, 1 h) blocks necroptosis through the suppression of RIPK3 function or signaling upstream of RIPK3 activation. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Viability AssayCell 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 AnalysisCell Line: HT-29 cells Concentration: 100 nM Incubation Time: 1 h Result: Completely abolished phosphorylation of RIPK1, RIPK3, and MLKL. ImmunofluorescenceCell Line: HT-29 cells Concentration: 100 nM Incubation Time: 1 h Result: Prevented generation of RIPK3 puncta. 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 . PK68 (1 mg/kg, i.p.) ameliorates TNF-induced systemic inflammatory response syndrome . 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 . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: C57BL/6 mice 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 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) T max (hr) 0.5 C max (ng/mL) 2423 AUC 0-24 (ng/mL•hr) 4821 1588 AUCINF (ng/mL•hr) 4897 1590 t 1/2 (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 Model: C57BL/6 mice Dosage: 1 mg/kg Administration: 1 mg/kg, i.p. Result: Provided effective protection against TNFα-induced lethal shock. Animal Model: C57BL/6 mice 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. Form:Solid IC50& Target:RIPK1 90 nM (IC 50 ) RIPK1 23 nM (EC 50 )

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