GSK621 is a novel, potent and selective activator of AMP-activated protein kinase (AMPK) with potential antitumor activity. It spares healthy hematopoietic progenitors while selectively killing acute myeloid leukemia (AML) cells. Both in vitro and in vivo tests revealed strong antiproliferative activity and high antitumor efficacy.
Physicochemical Properties
| Molecular Formula | C26H20N3O5CL |
| Molecular Weight | 489.907 |
| Exact Mass | 489.109 |
| Elemental Analysis | 2934.99.9001 |
| CAS # | 1346607-05-3 |
| Related CAS # | 1346607-05-3 |
| PubChem CID | 54577153 |
| Appearance | Off-white to light yellow solid powder |
| Density | 1.4±0.1 g/cm3 |
| Index of Refraction | 1.674 |
| LogP | 4.04 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 35 |
| Complexity | 778 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | COC1C=CC=C(N2C(=O)NC3=C(N(C(=C3)Cl)C3=CC=C(C4=CC=CC(OC)=C4O)C=C3)C2=O)C=1 |
| InChi Key | KURYSXLJGKKDHT-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C26H20ClN3O5/c1-34-18-6-3-5-17(13-18)30-25(32)23-20(28-26(30)33)14-22(27)29(23)16-11-9-15(10-12-16)19-7-4-8-21(35-2)24(19)31/h3-14,31H,1-2H3,(H,28,33) |
| Chemical Name | 6-chloro-5-[4-(2-hydroxy-3-methoxyphenyl)phenyl]-3-(3-methoxyphenyl)-1H-pyrrolo[3,2-d]pyrimidine-2,4-dione |
| Synonyms | GSK-621; GSK621; GSK 621 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | AMPK |
| ln Vitro | GSK621 significantly increases AMPKα T172 phosphorylation, a sign of AMPK activation, in both AML cell lines and primary AML samples. GSK621 inhibits the proliferation of all 20 cell lines in the study, with IC50 values ranging from 13 to 30 μM, and increases apoptosis in 17 (85%) of the lines. Additionally, GSK621 activates autophagy, which also plays a role in AML cell death.[1] |
| ln Vivo | GSK621 (30 mg/kg, i.p.) reduces leukemia growth and significantly increases survival in nude mice with MOLM-14 xenografts by increasing AMPK activity and inducing apoptosis.[1] |
| Enzyme Assay | HEPG2 cells are exposed to increasing doses of A-769662 or GSK621, and the phosphorylation of ACC S79 is measured using a commercial ELISA kit as a stand-in for the activation of AMPK. |
| Cell Assay | Twenty AML cell lines are subjected to log10 dilutions of GSK621, and CellTiter-Glo?assay is used to assess relative viability. Using the Prism software, the IC50 of GSK621 for each of these 20 cell lines is calculated and shown as log[C], where [C] is expressed in mol/l (M). Five different cell lines are represented in the results for each panel. |
| Animal Protocol |
NUDE Mice bearing MOLM-14 Xenografts 30 mg/kg, twice daily i.p. |
| References |
[1]. Cell Rep. 2015 Jun 9;11(9):1446-57. |
Solubility Data
| Solubility (In Vitro) |
DMSO: ~97 mg/mL (~198.0 mM) Water: <1 mg/mL Ethanol: <1 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: 1.25 mg/mL (2.55 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.25 mg/mL (2.55 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 1.25 mg/mL (2.55 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 2% DMSO+30% PEG 300+5% Tween 80+ddH2O: 5mg/mL Solubility in Formulation 5: 10 mg/mL (20.41 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0412 mL | 10.2060 mL | 20.4119 mL | |
| 5 mM | 0.4082 mL | 2.0412 mL | 4.0824 mL | |
| 10 mM | 0.2041 mL | 1.0206 mL | 2.0412 mL |