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编 号：F755548
分子式：C49H55FN6O9
分子量：890.99
分子式：C49H55FN6O9
分子量：890.99
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CAS No: 2759420-43-2
产品详情
生物活性：
NU223612 is a potent PROTAC (PROTACs) that degrades indoleamine 2,3-dioxygenase 1 (IDO1) (Indoleamine 2,3-Dioxygenase (IDO)) with a Kd of 640 nM. NU223612 potently degrades the IDO1 protein through CRBN-mediated proteasomal degradation. NU223612 is bound to CRBN with an affinity of 290 nM. NU223612 can cross the blood-brain barrier (BBB).
体内研究：
NU223612 (25 mg/kg; i.p.; once) decreases IDO1 protein in C57BL/6 with mIDO1 cDNA-expressing GL261 cells.NU223612 (25 mg/kg; i.p.; 5 days/week; for 3 weeks) leads to an increase in median overall survival as well as longer-term survival for up to 45 days post-tumor cell injection.Mass spectrometry analysis of NU223612 (25 mg/kg; i.p.; once) shows a Cmax of 2 μM and a half-life of 8.3 h in brain tissue. In plasma, Cmax is 365 μM and the half-life is 2.5 h. The binding of NU223612 to mouse brain homogenate using a 6 h equilibrium dialysis shows NU223612 to be 99.8% bound.Half-life, AUC, and?Cmax?of?NU223612?in serum and brain samples. Plasma Brain
half-lifr (h)2.58.3
AUC0-24 (μM?h)5827
Cmax (μM)3652
Animal Model:Male C57BL/6 mice bearing GL261 cells
Dosage:25 mg/kg
Administration:i.p.; once
Result:Decreased IDO1 protein by >70% within 2 h post-treatment and remains low for up to 24 h.
Animal Model:8 week old C57BL/6 wild-type (WT) mice are intracranially engrafted with luciferase-modified GL261 cells (GL261-luc.)
Dosage:25 mg/kg
Administration:i.p.; 5 days/week; for 3 weeks
Result:Led to an increase in median overall survival as well as longer-term survival for up to 45 days post-tumor cell injection.
体外研究：
NU223612 (0.1-10 μM; 24 h) decreases IDO1 protein levels dose-dependently.A DC50 (the concentration of the NU223612 at which 50% of the IDO1 protein is degraded) of 0.3290 μM and 0.5438 μM in U87 and GBM43 cells is determined, respectively.NU223612 degrades IDO1 protein in multiple cell types, such as CD18 and PANC-1 human pancreatic cancer cells, OVCAR5 and SKOV3 human ovarian cancer cells, PC3 human prostate cancer cells, and the syngeneic GL261 mouse IDO1 cDNA-expressing (IDO1-O/E) glioma cell line.NU223612 equally degrades IDO1 protein levels in both the cytoplasmic and nuclear intracellular compartments in human GBM cells. NU223612 is able to penetrate subcellular compartments.NU223612 dose-dependently inhibits IDO1 enzyme activity resulting in decreased Kyn levels in cultured IFNγ-stimulated GBM cells. NU223612 inhibits both IDO1-mediated tryptophan metabolism as well as IDO1 non-enzyme-mediated NF-κB p65 transcription factor DNA binding activity.
NU223612 is a potent PROTAC (PROTACs) that degrades indoleamine 2,3-dioxygenase 1 (IDO1) (Indoleamine 2,3-Dioxygenase (IDO)) with a Kd of 640 nM. NU223612 potently degrades the IDO1 protein through CRBN-mediated proteasomal degradation. NU223612 is bound to CRBN with an affinity of 290 nM. NU223612 can cross the blood-brain barrier (BBB).
体内研究：
NU223612 (25 mg/kg; i.p.; once) decreases IDO1 protein in C57BL/6 with mIDO1 cDNA-expressing GL261 cells.NU223612 (25 mg/kg; i.p.; 5 days/week; for 3 weeks) leads to an increase in median overall survival as well as longer-term survival for up to 45 days post-tumor cell injection.Mass spectrometry analysis of NU223612 (25 mg/kg; i.p.; once) shows a Cmax of 2 μM and a half-life of 8.3 h in brain tissue. In plasma, Cmax is 365 μM and the half-life is 2.5 h. The binding of NU223612 to mouse brain homogenate using a 6 h equilibrium dialysis shows NU223612 to be 99.8% bound.Half-life, AUC, and?Cmax?of?NU223612?in serum and brain samples. Plasma Brain
half-lifr (h)2.58.3
AUC0-24 (μM?h)5827
Cmax (μM)3652
Animal Model:Male C57BL/6 mice bearing GL261 cells
Dosage:25 mg/kg
Administration:i.p.; once
Result:Decreased IDO1 protein by >70% within 2 h post-treatment and remains low for up to 24 h.
Animal Model:8 week old C57BL/6 wild-type (WT) mice are intracranially engrafted with luciferase-modified GL261 cells (GL261-luc.)
Dosage:25 mg/kg
Administration:i.p.; 5 days/week; for 3 weeks
Result:Led to an increase in median overall survival as well as longer-term survival for up to 45 days post-tumor cell injection.
体外研究：
NU223612 (0.1-10 μM; 24 h) decreases IDO1 protein levels dose-dependently.A DC50 (the concentration of the NU223612 at which 50% of the IDO1 protein is degraded) of 0.3290 μM and 0.5438 μM in U87 and GBM43 cells is determined, respectively.NU223612 degrades IDO1 protein in multiple cell types, such as CD18 and PANC-1 human pancreatic cancer cells, OVCAR5 and SKOV3 human ovarian cancer cells, PC3 human prostate cancer cells, and the syngeneic GL261 mouse IDO1 cDNA-expressing (IDO1-O/E) glioma cell line.NU223612 equally degrades IDO1 protein levels in both the cytoplasmic and nuclear intracellular compartments in human GBM cells. NU223612 is able to penetrate subcellular compartments.NU223612 dose-dependently inhibits IDO1 enzyme activity resulting in decreased Kyn levels in cultured IFNγ-stimulated GBM cells. NU223612 inhibits both IDO1-mediated tryptophan metabolism as well as IDO1 non-enzyme-mediated NF-κB p65 transcription factor DNA binding activity.
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