1454585-06-8
1454585-06-8 structure
- Name: SR 3029
- Chemical Name: N-[(6,7-Difluoro-1H-benzimidazol-2-yl)methyl]-9-(3-fluorophenyl)-2-(4-morpholinyl)-9H-purin-6-amine
- CAS Number: 1454585-06-8
- Molecular Formula: C23H19F3N8O
- Molecular Weight: 480.445
- Catalog: Signaling Pathways Cell Cycle/DNA Damage Casein Kinase
- Create Date: 2018-02-22 01:22:00
- Modify Date: 2024-01-02 16:05:30
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SR-3029 is a potent and ATP competitive CK1δ and CK1ε inhibitor, with IC50s of 44 nM and 260 nM, respectively, and Kis of 97 nM for both kinases.
| Name | N-[(6,7-Difluoro-1H-benzimidazol-2-yl)methyl]-9-(3-fluorophenyl)-2-(4-morpholinyl)-9H-purin-6-amine |
|---|---|
| Synonyms |
9H-Purin-6-amine, N-[(6,7-difluoro-1H-benzimidazol-2-yl)methyl]-9-(3-fluorophenyl)-2-(4-morpholinyl)-
N-[(6,7-Difluoro-1H-benzimidazol-2-yl)methyl]-9-(3-fluorophenyl)-2-(4-morpholinyl)-9H-purin-6-amine SR-3029 |
| Description | SR-3029 is a potent and ATP competitive CK1δ and CK1ε inhibitor, with IC50s of 44 nM and 260 nM, respectively, and Kis of 97 nM for both kinases. |
|---|---|
| Related Catalog | |
| Target |
CKIδ:44 nM (IC50) CKIϵ:260 nM (IC50) CDK6/cyclin D3:427 nM (IC50) CDK6/cyclin D1:428 nM (IC50) CDK4/cyclin D3:368 nM (IC50) CDK4/cyclin D1:576 nM (IC50) FLT3:3000 nM (IC50) |
| In Vitro | SR-3029 is a potent CK1δ/CK1ε inhibitor, with IC50s of 44 nM and 260 nM, respectively. SR-3029 is ATP competitive, with Kis of 97 nM for CK1δ/CK1ε. SR-3029 also blocks CDK6/cyclin D3, CDK6/cyclin D1, CDK4/cyclin D3, CDK4/cyclin D1 and FLT3, with IC50s of 427, 428, 368, 576, and 3000 nM, respectively. SR-3029 shows inhibitory effects on A375 cells, with an EC50 of 86 nM[1]. CK1δ is a necessary and sufficient driver of Wnt/β-catenin signaling in human breast cancer. SR-3029 shows less potent activities against MCF7 and T47D breast cancer cells and the MCF10A cell line, which express low amounts of CK1δ[2]. |
| In Vivo | SR-3029 (20 mg/kg daily i.p.) exibits anti-tumor effects in rthotopic MDA-MB-231, MDA-MB-468 (TNBC), SKBR3 and BT474 (HER2+) tumor xenografts with no overt toxicity in mice. SR-3029 (20 mg/kg daily i.p.) also effectively inhibits the growth of tumor in primary patient-derived xenograft (PDX) models. In addition, SR-3029 (20 mg/kg, i.p.) strongly reduces the expression of nuclear β-catenin in tumors of mice[2]. |
| Kinase Assay | Briefly, final assay concentrations for CK1δ, Ulight peptide substrate (ULight-Topo-Ila(Thr1342) peptide) and ATP are 2 nM, 200 nM and 20 μM respectively. The reaction is performed at room temperature in a 10 μL final volume (384-well low volume plate) containing the following: 50 mM Hepes, pH 7.5, 5 mM MgCl2, 0.1 mg/mL bovine serum albumin, 1 mM dl-dithiothreitol, 0.01% Triton X-100 and 1% DMSO. After 10 min, the reaction is terminated by addition of 10 μL of 4 nM Eu-anti-p-Topo-Ila in Lance Detection Buffer. The fluorescent signal is detected using a plate reader. 10 point does-response curves with 3-fold dilutions starting from 10 μM for each compound (SR-3029) is generated in duplicate and data fit to a four parameter logistic[1]. |
| Cell Assay | Human A375 melanoma cells are cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin and 1× MEM Non-Essential Amino Acids at 37°C, 5% CO2. To evaluate the anti-proliferative activity of newly synthesized CK1δ/ε inhibitors, each compound (SR-3029) is subjected to MTT assays against A375 melanoma cells and their EC50 values are determined. Briefly, A375 melanoma cells are plated into a 96-well plate and treated with a series of concentrations of each new inhibitor, vehicle (DMSO) or with SR-3029 or SR-1277 (positive controls). MTT assays are performed four days after treatment and data are analyzed using the GraphPad Prism5[1]. |
| Animal Admin | Stable pools of MDA-MB-231-Luc, MDA-MB-231, MDA-MB-468, SKBR3, or BT474 cells are established by injection of 2 × 106 cancer cells into the mammary fat pads of 6-week-old female athymic nude mice. Establishment of BCM-4013 patient-derived xenografts is performed. Briefly, fresh xenograft tumor fragments (∼1 mm3) are transplanted into the cleared mammary fat pad of recipient SCID/Bg mice. Mice are treated with SR-3029 or vehicle (10:10:80, DMSO:Tween-80:Water) at 20 mg/kg daily by i.p. injection. Tumor volumes are measured as the indicated intervals using calipers or by luminescence imaging with the IVIS 100 imager after subcutaneous injection of luciferin (15 mg/mL). Average radiance (p/s/cm2/sr) is determined from tumor region-of-interest (ROI) using Living-Image analysis software[2]. |
| References |
| Density | 1.6±0.1 g/cm3 |
|---|---|
| Boiling Point | 818.7±75.0 °C at 760 mmHg |
| Molecular Formula | C23H19F3N8O |
| Molecular Weight | 480.445 |
| Flash Point | 448.9±37.1 °C |
| Exact Mass | 480.163391 |
| LogP | 1.53 |
| Appearance | white solid |
| Vapour Pressure | 0.0±3.0 mmHg at 25°C |
| Index of Refraction | 1.748 |
| Storage condition | -20℃ |