Epiblastin A
目录号 : GC43618An inhibitor of CK1α, CK1δ, and CK1ε
Cas No.:16470-02-3
Sample solution is provided at 25 µL, 10mM.
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Epiblastin A is an ATP-competitive inhibitor of the casein kinase 1 (CK1) isoforms α, δ, and ε (IC50s = 8.9, 0.5, and 4.7 μM, respectively). [1] It is selective for CK1α, CK1δ, and CK1ε at concentrations below 10 μM, however, it also inhibits BRSK1, EEF2K, EGFR, MNK-2, and RIPK2 (IC50s = 24-45 μM). Epiblastan A reduces immunoprecipitation of CK1α, CK1δ, and CK1ε from HCT116 cell lysates in a concentration-dependent manner. It induces reprogramming of mouse epiblast stem cells (mEpiSCs) into embryonic stem cells (ESCs) 8-fold more efficiently than triamterene .
Reference:
[1]. Ursu, A., Illich, D.J., Takemoto, Y., et al. Epiblastin A induces reprogramming of epiblast stem cells into embryonic stem cells by inhibition of Casein Kinase 1. Cell Chem. Biol. 23(4), 494-507 (2016).
Cas No. | 16470-02-3 | SDF | |
化学名 | 6-(3-chlorophenyl)-2,4,7-pteridinetriamine | ||
Canonical SMILES | NC1=NC2=NC(N)=NC(N)=C2N=C1C3=CC(Cl)=CC=C3 | ||
分子式 | C12H10ClN7 | 分子量 | 287.7 |
溶解度 | Soluble in DMSO & DMF | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 3.4758 mL | 17.3792 mL | 34.7584 mL |
5 mM | 0.6952 mL | 3.4758 mL | 6.9517 mL |
10 mM | 0.3476 mL | 1.7379 mL | 3.4758 mL |
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Epiblastin A Induces Reprogramming of Epiblast Stem Cells Into Embryonic Stem Cells by Inhibition of Casein Kinase 1
Cell Chem Biol 2016 Apr 21;23(4):494-507.PMID:27049670DOI:10.1016/j.chembiol.2016.02.015.
The discovery of novel small molecules that induce stem cell reprogramming and give efficient access to pluripotent stem cells is of major importance for potential therapeutic applications and may reveal novel insights into the factors controlling pluripotency. Chemical reprogramming of mouse epiblast stem cells (EpiSCs) into cells corresponding to embryonic stem cells (cESCs) is an inefficient process. In order to identify small molecules that promote this cellular transition, we analyzed the LOPAC library in a phenotypic screen monitoring Oct4-GFP expression and identified triamterene (TR) as initial hit. Synthesis of a TR-derived compound collection and investigation for reprogramming of EpiSCs into cESCs identified casein kinases 1 (CK1) α/δ/ɛ as responsible cellular targets of TR and unraveled the structural parameters that determine reprogramming. Delineation of a structure-activity relationship led to the development of Epiblastin A, which engages CK1 isoenzymes in cell lysate and induces efficient conversion of EpiSCs into cESCs.
CK1α-targeting inhibits primary and metastatic colorectal cancer in vitro, ex vivo, in cell-line-derived and patient-derived tumor xenograft mice models
Transl Cancer Res 2020 Mar;9(3):1903-1913.PMID:35117537DOI:10.21037/tcr.2020.02.13.
Background: Colorectal cancer (CRC) remains a leading cause of cancer-related deaths globally. Despite improved understanding of its initiation and progression, and advances in diagnostic or therapeutic strategies, the treatment of metastatic CRC remains a clinical challenge, necessitating identification of novel efficacious therapeutics with little/no toxicity to non-tumor colorectal cells. The present study investigated the effect of Epiblastin A, an adenosine triphosphate (ATP)-mediated competitive inhibitor of casein kinase 1α (CK1α) on the viability, proliferation, and oncogenicity of CRC cells. Methods: Comparative evaluation of the effect of Epiblastin A on CK1α in fetal human normal colonic mucosa (FHC) and CRC (HCT116, HT29, DLD1) cell lines, using western blot, immunohistochemical staining, real-time polymerase chain reaction (RT-PCR), and sulforhodamine B (SRB) cytotoxicity assays. Primary culture cells, patient-derived xenograft (PDX), and tumor xenograft mice CRC models were also employed. Kaplan-Meier plots were used for survival analysis of our CRC cohort. Results: CRC cells aberrantly express CK1α at mRNA and protein levels. This overexpression of CK1α is strongly associated with worse 5-year overall survival (OS) in patients with CRC. Epiblastin A inhibits CK1α and compared to its apparent non-effect on FHC cells regardless of concentration, it elicits significant dose-dependent inhibition of the viability of HT29, HCT116, and DLD1 cells with a 48 h IC50 of 6.8, 5.0, and 3.2 μM, respectively. The expression of CK1α in CRC primary cultures and PDX samples, significantly correlated with Ki-67 expression, and both were attenuated by Epiblastin A. We also observed that the effect of 5 mg/kg Epiblastin A on tumor volume, and body weight in the CRC PDX mice models, was similar to that of 5 mg/kg Cetuximab over the time-course of our in vivo study. In DLD1-derived tumor xenograft mice, Epiblastin A with very mild effect on mice body weight, suppressed tumor volume and tumor weight in a CK1α-dependent manner (P=0.024). Conclusions: Our results demonstrate the efficacy of Epiblastin A in CRC and its potential as a putative small-molecule inhibitor of CK1α and Ki-67 signaling, which are relevant in the CRC initiation, progression and prognosis.