| CAS NO: | 1951483-29-6 |
| 规格: | ≥98% |
| 包装 | 价格(元) |
| 2mg | 电议 |
| 5mg | 电议 |
| 10mg | 电议 |
| 25mg | 电议 |
| 50mg | 电议 |
| 100mg | 电议 |
| 250mg | 电议 |
| Molecular Weight (MW) | 453.56 |
|---|---|
| Formula | C22H27N7O2S |
| CAS No. | 1951483-29-6 |
| Storage | -20℃ for 3 years in powder form |
| -80℃ for 2 years in solvent | |
| Solubility (In vitro) | DMSO: 25 mg/mL |
| Water: < 1 mg/mL | |
| Ethanol: 15 mg/mL | |
| Chemical Name | 6,6-dimethyl-2-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-5-(2-morpholinoethyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-4-one |
| Synonyms | LY-3214996; LY3214996; LY 3214996; Temuterkib |
| SMILES Code | O=C(C(C=C(C1=NC(NC2=CC=NN2C)=NC=C1)S3)=C3C4(C)C)N4CCN5CCOCC5 |
| In Vitro | In vitro activity: LY3214996 is a highly potent and selective inhibitor of ERK1 and ERK2, with IC50 of 5 nM for ERK1/2 in biochemical assays. LY3214996 significantly inhibits cellular phospho-RSK1 in BRAF and RAS mutant cancer cell lines. In an unbiased tumor cell panel sensitivity profiling for inhibition of cell proliferation, tumor cells with MAPK pathway alterations including BRAF, NRAS or KRAS mutation are generally sensitivity to LY3214996. Kinase Assay: LY3214996 demonstrated an optimal balance of potency (hERK1 IC50 5 nM, hERK2 IC50 5nM, pRSK IC50 0.43 μM) and solubility Cell Assay: In an unbiased tumor cell panel sensitivity profiling for inhibition of cell proliferation, tumor cells with MAPK pathway alterations including BRAF, NRAS or KRAS mutation are generally sensitivity to LY3214996. |
|---|---|
| In Vivo | In tumor models (xenograft), LY3214996 inhibits PD biomarker phospho-p90RSK1 in tumors with the PD effects correlated with compound exposures and anti-tumor activities. LY3214996 shows either similar or superior anti-tumor activity as compared to other published ERK inhibitors in BRAF or RAS mutant cell lines and xenograft models. Oral administration of single-agent LY3214996 significantly inhibits tumor growth in vivo and is well tolerated in BRAF or NRAS mutant melanoma, BRAF or KRAS mutant colorectal, lung and pancreatic cancer xenografts or PDX models. In addition, LY3214996 has anti-tumor activity in a vemurafenib-resistant A375 melanoma xenograft model due to MAPK reactivation, may have potential for treatment of melanoma patients who have failed BRAF therapies. More importantly, LY3214996 can be combined with investigational and approved agents in preclinical models, particularly KRAS mutant models. Combination treatment of LY3214996 and CDK4/6 inhibitor abemaciclib is well tolerated and results in potent tumor growth inhibition or regression in multiple in vivo cancer models, including KRAS mutant colorectal and non-small cell lung cancers. LY3214996 has good PK properties (dog, AUCoral 23800 nM*hr, CL 12.1 mL/min/kg, bioavailability 75.4%), IVTI (TED50 =16 mg/kg pRSK1) and demonstrates significant in vivo efficacy in several human cancer xenograft models [1] |
| Animal model | Vemurafenib-resistant A375 melanoma xenograft model and multiple in vivo cancer models, including KRAS mutant colorectal and non-small cell lung cancers |
| Formulation & Dosage | For pharmacodynamic (PD) studies in HCT116 colorectal cancer xenograft model, animals were randomized into groups of 5 and dosed orally with LY3214996 in hydroxyethylcellulose 1% (w/v)/P80 0.25% (v/v)/antifoam 1510-US 0.05% (v/v) [2] |
| References | [1] Cancer Research 77(13 Supplement):3231-323 [2] Mol Cancer Ther. 2020 Feb;19(2):325-336. |
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