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    Prexasertib 2HCl (LY-2606368)
    Prexasertib 2HCl (LY-2606368)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0080
    CAS #: 1234015-54-3Purity ≥98%

    Description: Prexasertib 2HCl (also known as LY2606368) is the dihydrochloride salt of Prexasertib with potential anticancer activity. It is a novel, potent, selective and ATP competitive inhibitor of the CHK1 (checkpoint kinase 1) protein kinase with IC50 values of<1 nM and 8 nM for CHK1 and CHK2, respectively. CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Prexasertib as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of Prexasertib is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with Prexasertib results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Prexasertib shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. In conclusion, Prexasertib is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe.

    References:  2015 Sep;14(9):2004-13;  2017 Mar 1;7(3):473-483. 

    Related CAS: 1234015-55-4 (mesylate); 1234015-52-1 (free base); 1234015-57-6 (mesylate hydrate)   1234015-54-3 (2HCl)   2100300-72-7 (lactate hydrate)

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    Molecular Weight (MW) 438.31
    FormulaC₁₈H₂₁Cl₂N₇O₂
    CAS No.234015-54-3 (2HCl)
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: ≥ 60 mg/mL
    Water: < 1mg/mL
    Ethanol: < 1mg/mL
    Chemical Name5-((5-(2-(3-aminopropoxy)-6-methoxyphenyl)-1H-pyrazol-3-yl)amino)pyrazine-2-carbonitrile dihydrochloric acid
    SynonymsLY-2606368; LY 2606368; LY2606368; Prexasertib
    SMILES CodeNCCCOC(C=CC=C1OC)=C1C2=CC(NC3=NC=C(C#N)N=C3)=NN2.[H]Cl.[H]Cl


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    In Vitro

    In vitro activity: Prexasertib (also know LY2606368) is a novel, potent, selective and ATP competitive inhibitor of the CHK1 (checkpoint kinase 1) protein kinase with IC50 values of<1 nM and 8 nM for CHK1 and CHK2, respectively. CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Prexasertib as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of Prexasertib is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with Prexasertib results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Prexasertib shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. In summary, Prexasertib is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe.


    Kinase Assay: Prexasertib (LY2606368) potently and selectively inhibits CHK1 with an IC50 of<1 nM, and also inhibits CHK2, with an IC50 of 8 nM. LY2606368 has an EC50 of 1 nM for CHK1 activity through autophosphorylation of serine 296 and <31 nM for HT-29 CHK2 autophosphorylation (S516). LY2606368 potently abrogates the G2-M checkpoint activated by doxorubicin in p53-deficient HeLa cells with an EC50 of 9 nM. However, 100 nM LY2606368 does not inhibit PMA-stimulated RSK but instead weakly stimulates phosphorylation of S6 on serines 235/236. LY2606368 is broadly antiproliferative with IC50s of 3 nM, 3 nM, 10 nM, 37 nM, and 68 nM against U-2 OS, Calu-6, HT-29, HeLa, and NCI-H460 cell lines, respectively. LY2606368 (4 nM) results in a large shift in cell-cycle populations from G1 and G2-M to S-phase with an accompanied induction of H2AX phosphorylation in U-2 OS cells. LY2606368 (25 μM) exhibits inhibitory activities against proliferation of AGS and MKN1 cells. LY2606368 (20 nM) inhibits HR repair capacity DR-GFP cells. LY2606368 (5 nM) in combination with PARP inhibitor BMN673, displays synergistic anticancer effects in gastric cancer cells. 


    Cell Assay: Proliferation inhibition effect of CHK1 ablation, IR sensitivity, anticancer effect of BMN673 and LY2606368 are detected by MTS Cell Proliferation Colorimetric Assay Kit. Cells are seeded into 96 wells cell culture plate, then treated with indicated experiment conditions, then added 20 μL MTS reagent to each well subsequently, after incubated for 2 hours, cell viability of each well is detected on microplate reader at a wavelength of 490 nM. 

    In VivoPrexasertib (LY2606368) inhibited tumor growth in cancer xenografts when used as monotherapy and in combination with other agents. In an orthotopic SKOV3 ovarian cancer model, LY2606368 inhibited the growth of primary tumors and significantly reduce the incidence of metastases and ascites accumulation. LY2606368 also demonstrated efficacy in an SW1990 orthotopic pancreatic cancer model resulting in a 92% inhibition of primary tumor growth and the elimination of metastases to the lymphnode, spleen, and intestine
    Animal modelFemale CD-1 nu-/nu- mice
    Formulation & DosageDissolved in 20% Captisol (pH4); 15 mg/kg; s.c. injection
    References  2015 Sep;14(9):2004-13;  2017 Mar 1;7(3):473-483. 


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Prexasertib 2HCl


    Exposure to LY2606368 results in DNA damage during S-phase.  2015 Sep;14(9):2004-13.

     Prexasertib 2HCl


    The DNA damage effects of LY2606368 are dependent upon CDC25A and CDK2.


    Prexasertib 2HCl

    LY2606368 causes chromosomal fragmentation.  2015 Sep;14(9):2004-13.

     


     

    Prexasertib 2HCl

    LY2606368 causes DNA damage and growth inhibition in tumor xenografts.   2015 Sep;14(9):2004-13.

    Prexasertib 2HCl


    LY2606368 induces replication stress and depletes the pool of available RPA2 for binding to DNA.  2015 Sep;14(9):2004-13.

     Prexasertib 2HCl


    Chk1 inhibitor LY2606368 can induce DNA damage and apoptosis, and can suppress cell proliferation in gastric cancer cells.


    Prexasertib 2HCl

    LY2606368 can sensitize the anticancer effect of PARP inhibitor BMN673 in gastric cancer cells.  2017 Mar 1;7(3):473-483.

    Prexasertib 2HCl Chk1 inhibitor LY2606368 can suppress HR repair capacity.



    Prexasertib 2HCl

    LY2606368 and BMN673 combination has synergistic anticancer effect in gastric cancer PDX model.  2017 Mar 1;7(3):473-483.


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