NU223612 是一种有效的PROTAC(PROTACs)，可降解吲哚胺 2,3-双加氧酶 1 (IDO1) (Indoleamine 2,3-Dioxygenase (IDO))，Kd为 640 nM。NU223612 通过CRBN介导的蛋白酶体降解有效降解 IDO1 蛋白。NU223612 以 290 nM 的亲和力与 CRBN 结合。NU223612 可以穿过血脑屏障 (BBB)。
| 生物活性 | NU223612 is a potentPROTAC(PROTACs) that degradesindoleamine 2,3-dioxygenase1 (IDO1)(Indoleamine 2,3-Dioxygenase (IDO)) with aKdof 640 nM. NU223612 potently degrades theIDO1protein throughCRBN-mediated proteasomal degradation. NU223612 is bound to CRBN with an affinity of 290 nM. NU223612 can cross the blood-brain barrier (BBB)[1]. |
| IC50& Target[1] | |
体外研究
(In Vitro) | NU223612 (0.1-10 μM; 24 h) decreases IDO1 protein levels dose-dependently[1].
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[1].
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[1].
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[1].
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[1].
Western Blot Analysis[1] | Cell Line: | U87 and human GBM43 cells | | Concentration: | 0 μM, 0.1 μM, 1 μM, and 10 μM | | Incubation Time: | 24 h | | Result: | Decreased IDO1 protein levels dose-dependently. |
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体内研究
(In Vivo) | NU223612 (25 mg/kg; i.p.; once) decreases IDO1 protein in C57BL/6 with mIDO1 cDNA-expressing GL261 cells[1].
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[1].
Mass spectrometry analysis of NU223612 (25 mg/kg; i.p.; once) shows a Cmaxof 2 μM and a half-life of 8.3 h in brain tissue. In plasma, Cmaxis 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[1].
Half-life, AUC, and Cmax of NU223612 in serum and brain samples[1].
| Plasma | Brain | | half-lifr (h) | 2.5 | 8.3 | | AUC0-24(μM?h) | 582 | 7 | | Cmax(μM) | 365 | 2 |
| Animal Model: | Male C57BL/6 mice bearing GL261 cells[1] | | 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.)[1] | | 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. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | Please store the product under the recommended conditions in the Certificate of Analysis. |
