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| Cas No.: | 2093388-62-4 |
| Chemical Name: | 4-((3-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)amino)-7-(3,5-dimethylisoxazol-4-yl)-N-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)-6-methoxy-9H-pyrimido[4,5-b]indole-2-carboxamide |
| Synonyms: | ZBC 260;ZBC260;BETd 260 |
| SMILES: | N1C2=C(C=C(OC)C(C3=C(C)ON=C3C)=C2)C2=C(NC3N(CC)N=C(C4CC4)C=3)N=C(C(NCCCCCC3=CC=CC4=C3CN(C3CCC(=O)NC3=O)C4=O)=O)N=C12 |
| Formula: | C43H46N10O6 |
| M.Wt: | 798.905 |
| Purity: | >98% |
| Sotrage: | 2 years -20°C Powder, 2 weeks 4°C in DMSO, 6 months -80°C in DMSO |
| Publication: | [1]. Zhou B, et al. Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression. J Med Chem. 2018 Jan 25;61(2):462-481. |
| Description: | BETd-260 is a potent BET degrader based on PROTAC technology, with an IC50 of 30 pM against BRD4 protein in RS4;11 leukemia cell line. |
| Target: | IC50: 30 pM (BRD4, RS4;11 leukemia cells)[1] PROTAC |
| In Vivo: | BETd-260 (5 mg/kg, i.v., every other day, thrice a week for 3 weeks) causes rapid tumor regression with a maximum of >90% regression in mice bearing RS4;11 xenograft tumors, and with no body weight loss or other signs of toxicity in mice. BETd-260 (5 mg/kg, i.v.) degrades the BRD2, BRD3, and BRD4 proteins for more than 24 h, with robust cleavage of PARP and caspase-3, and strong down-regulation of c-Myc protein in RS4;11 xenograft mice model[1]. |
| In Vitro: | BETd-260 is a potent BET degrader based on PROTAC technology, with an IC50 of 30 pM for BRD4 protein in RS4;11 leukemia cell line. BETd-260 (ZBC260; Compound 23) shows inhibitory activity against the growth of RS4;11 leukemia cells and MOLM-13 cells with IC50s of 51 pM and 2.2 nM, respectively, and induces apoptosis in both RS4;11 and MOLM-13 cell lines at 3-10 nM[1]. |
| Cell Assay: | In cell growth experiments, cells are seeded in 96-well cell culture plates at a density of 10000−20000 cells/well in 100 μL of culture medium. BETd-260 is serially diluted in the appropriate medium, and 100 μL of the diluted solution containing BETd-260 is added to the appropriate wells of the cell plate. After addition of BETd-260, the cells are incubated for 4 days at 37°C in an atmosphere of 5% CO2. Cell growth is evaluated by a lactate dehydrogenase-based WST-8 assay using a multimode microplate reader. The WST-8 reagent is added to the plate, incubated for at least 1 h, and read at 450 nm. The readings are normalized to the DMSO-treated cells, and the IC50 is calculated by nonlinear regression analysis using GraphPad Prism 6 software[1]. |
| Animal Administration: | Mice[1] To develop xenograft tumors, 5 × 106 RS4;11 cells with 50% Matrigel are injected subcutaneously on the dorsal side of severe combined immunodeficient (SCID) mice, one tumor per mouse. When tumors reach appr 100 mm3, mice are randomly assigned to BETd-260 treatment and vehicle control groups. Animals are monitored daily for any signs of toxicity and weighed 2-3 times per week during the treatment and weighed at least weekly after BETd-260 treatment end. Tumor size is measured 2-3 times per week by electronic calipers during the treatment period and at least weekly after the treatment is end. Tumor volume is calculated as V = LW2/2, where L is the length and W is the width of the tumor[1]. |
| References: | [1]. Zhou B, et al. Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression. J Med Chem. 2018 Jan 25;61(2):462-481. |