NU223612

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)[1].

Research Areas >> Cancer

Signaling Pathways >> Metabolic Enzyme/Protease >> Indoleamine 2,3-Dioxygenase (IDO)

Signaling Pathways >> PROTAC >> PROTAC

Research Areas >> Neurological Disease

Cereblon

IDO1:640 nM (Kd)

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.

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 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[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.

[1]. Lakshmi R Bollu, et al. Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma. J Med Chem. 2022 Nov 21.