SEL120-34A hydrochloride (SEL-120-34A; SEL12034A) is a novel, potent and selective ATP-competitiveinhibitor of CDK8(Cyclin-dependent kinase 8) with anticancer activity. It binds to the Mediator complex to control transcription. The kinase activities of CDK8/CycC and CDK19/CycC complexes are inhibited by SEL120-34A, with IC50s of 4.4 nM and 10.4 nM, respectively, and a Kdof 3 nM for CDK8. According to X-ray crystallography, SEL120-34A is a type I inhibitor that forms hydrophobic complementarities within the protein's front pocket and halogen bonds with its hinge region. In vitro, SEL120-34A prevents cancer cells' phosphorylation of STAT1 S727 and STAT5 S726. In vivo, the predominant mechanism of action has consistently been observed to be the regulation of STATs- and NUP98-HOXA9-dependent transcription. AML cells with increased STAT5 S726 levels and stem cell features responded differently to treatment with the compound. On the other hand, resistant cells demonstrated lineage commitment and tested negative for activated STAT5. Significant STAT5 S726 repression was correlated with in vivo efficacy in xenotransplanted AML models. Good pharmacokinetics, established safety, and in vivo effectiveness support SEL120-34A'scontinuedclinical development as a tailored treatment strategy for AML.
Physicochemical Properties
| Molecular Formula | C15H19BR2CLN4 |
| Molecular Weight | 450.599160432816 |
| Exact Mass | 449.964 |
| Elemental Analysis | C, 39.98; H, 4.25; Br, 35.47; Cl, 7.87; N, 12.43 |
| CAS # | 1609452-30-3 |
| Related CAS # | SEL120-34A monohydrochloride;2443816-41-7;SEL120-34A;1609522-33-9 |
| PubChem CID | 73776232 |
| Appearance | White to off-white solid powder |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 3 |
| Rotatable Bond Count | 1 |
| Heavy Atom Count | 22 |
| Complexity | 390 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | GQXLWUCQESKBSC-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C15H18Br2N4.ClH/c1-9-11(16)12(17)10-3-2-6-21-14(10)13(9)19-15(21)20-7-4-18-5-8-20;/h18H,2-8H2,1H3;1H |
| Chemical Name | 6,7-dibromo-5-methyl-2-piperazin-1-yl-1,3-diazatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraene;hydrochloride |
| Synonyms | SEL120-34A monohydrochloride; SEL-120-34A; SEL12034A; SEL120-34A HCl; SEL 120-34A; SEL 12034A; SEL-12034A |
| 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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 | CDK8/CycC (IC50 = 4.4 nM); CDK19/CycC (IC50 = 10.4 nM); CDK9/cycT (IC50 = 1070 nM) |
| ln Vitro | SEL120-34A HCl is an ATP-competitive, selective inhibitor of CDK8, with IC50 values of 10.4 nM for CDK19/CycC and 4.4 nM for CDK8/CycC. SEL120-34A HCl only weakly suppresses CDK9 (IC50, 1070 nM) and exhibits no discernible inhibition on CDK1, 2, 4, 6, 5, 7, or 6. According to the effective inhibition range of STAT1 S727 and STAT5 S726, SEL120-34A HCl is active against a panel of AML cell lines (GI50<1 μM), including SKNO-1, KG-1, HEL-60, MOLM-16, MV-4-11, OciAML-2, MOLM-6, and OciAML-3 cells.[1] |
| ln Vivo | SEL120-34A (30, 60 mg/kg, p.o.) suppresses tumor growth in mice bearing MV4-11 cancer cells. Moreover, oral administration of 30 mg/kg stops the growth of KG-1-derived tumors[1]. |
| Cell Assay | At 2.5 ×105 per well, HCT-116 are seeded onto 6-well plates. The next day, cells are starved of 0.5% FBS for 24 hours to synchronize them, and then they are pretreated for 1 hour with either 0.1% DMSO or SEL120-34A at the indicated concentration. Finally, they are supplemented with 10% FBS, IFNg, or IFNa in the presence of the inhibitor for 4 hours. The cells undergo a 5-minute centrifugation at 1300 rpm in 4°C, a single ice-cold PBS wash, and storage at -80°C. |
| Animal Protocol |
SCID/beige C.B17 female mice xenografted with Colo-205 tumors 5, 15, 30 and 60 mg/kg BID oral |
| References |
[1]. SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains. Oncotarget. 2017 May 16;8(20):33779-33795. |
| Additional Infomation | CDK8/19 Inhibitor RVU120 is an orally bioavailable inhibitor of cyclin-dependent kinases 8 and 19 (CDK8/19), with potential antineoplastic and chemoprotective activities. Upon oral administration, CDK8/19 inhibitor RVU120 targets, binds to and inhibits the activity of CDK8/19, which prevents activation of CDK8/19-mediated oncogenic signaling pathways, blocks selective transcription of various tumor-promoting genes, and inhibits proliferation of CDK8/19-overexpressing tumor cells. CDK8/19, serine/threonine kinases involved in the regulation of the cell cycle, are overexpressed in certain cancer cell types and play key roles in tumor cell proliferation. |
Solubility Data
| Solubility (In Vitro) |
Water: ~90 mg/mL Ethanol: ˂1 mg/mL DMSO: 1~62.5 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (Infinity mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 20.8 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: ≥ 2.08 mg/mL (Infinity 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), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 3: 2.08 mg/mL (Infinity mM) 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2193 mL | 11.0963 mL | 22.1926 mL | |
| 5 mM | 0.4439 mL | 2.2193 mL | 4.4385 mL | |
| 10 mM | 0.2219 mL | 1.1096 mL | 2.2193 mL |