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5mg |
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25mg |
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Purity: ≥98%
Prexasertib (also known as 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. The multifunctional protein kinase CHK1 is essential for the regulation of the number of active replication forks in cells as well as the response of the cells to damage to DNA. Because CHK1 establishes DNA damage checkpoints in the cell cycle, CHK1 inhibitors are currently being studied as potential chemopotentiating agents. When taken by itself, prexasertib breaks double-stranded DNA and eliminates the DNA damage checkpoints' defenses. Prexasertib's action is reliant on CHK1 inhibition and the ensuing rise in CDC25A activation of CDK2, which raises the quantity of replication forks while decreasing their stability. Prexasertib treatment causes TUNEL and pH2AX-positive double-stranded DNA breaks to rapidly manifest in the S-phase cell population. Prexasertib significantly inhibits tumor growth in xenograft tumor models with comparable efficacy. To sum up, Prexasertib is a powerful example of a new class of cancer treatment medications that works by causing a replication catastrophe.
Targets |
Chk1 (Ki = 0.9 nM); Chk1 (IC50 <1 nM); Chk2 (IC50 = 8 nM)
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ln Vitro |
Prexasertib (LY2606368) inhibits ARK5 (IC50=64 nM), BRSK2 (IC50=48 nM), SIK (IC50=42 nM), and MELK (IC50=38 nM). DNA deterioration caused by LY2606368 requires both CDK2 and CDC25A[1].
Prexasertib (8-250 nM; pre-treated for 15 minutes) causes damage to DNA during the S-phase in HT-29 cells[1]. Prexasertib (4 nM; 24 hours) causes a significant change in cell cycle populations from G1 and G2-M to S-phase, along with an increase in H2AX phosphorylation[1]. Prexasertib (33 nM; for 12 hours) causes the fragmentation of chromosomes in HeLa cells. Replication stress is induced by prexasertib Mesylate Hydrate (100 nM; 0.5 to 9 hours), which also reduces the amount of RPA2 that is available for DNA binding[1]. |
ln Vivo |
Prexasertib (LY2606368; 1-10 mg/kg; SC; twice daily for 3 days, rest 4 days; for three cycles) inhibits the growth of tumor xenografts[1].
Prexasertib (15 mg/kg; SC) phosphorylates RPA2 (S4/S8) and H2AX (S139), inhibiting CHK1 in the blood[1]. |
Enzyme Assay |
Prexasertib (LY2606368) inhibits CHK1 and CHK2 with IC50 values less than 1 nM and 8 nM, respectively, with a strong and specific potency. For CHK1 activity via serine 296 autophosphorylation, LY2606368 has an EC50 of 1 nM, and for HT-29 CHK2 autophosphorylation, it is <31 nM (S516). With an EC50 of 9 nM, LY2606368 potently inhibits the G2-M checkpoint that doxorubicin has activated in p53-deficient HeLa cells. Still, 100 nM Instead of weakly inhibiting PMA-stimulated RSK, LY2606368 slightly increases the phosphorylation of S6 on serines 235/236. LY2606368 exhibits broad antiproliferative activity against U-2 OS, Calu-6, HT-29, HeLa, and NCI-H460 cell lines, exhibiting IC50 values of 3 nM, 3 nM, 10 nM, 37 nM, and 68 nM, respectively. Induction of H2AX phosphorylation and a significant shift in cell-cycle populations from G1 and G2-M to S-phase are both brought about by LY2606368 (4 nM) in U-2 OS cells. The anti-proliferative properties of AGS and MKN1 cells are demonstrated by LY2606368 (25 μM). HR repair capacity in DR-GFP cells is inhibited by LY2606368 (20 nM). When combined with the PARP inhibitor BMN673, LY2606368 (5 nM) exhibits synergistic anticancer effects in gastric cancer cells.
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Cell Assay |
The MTS Cell Proliferation Colorimetric Assay Kit measures the anticancer effects of BMN673 and LY2606368, the proliferation inhibition effect of CHK1 ablation, and IR sensitivity. After seeding cells into 96-well cell culture plates, each well is treated according to the experiment conditions specified. After two hours of incubation, the cell viability of each well is measured using a microplate reader set to detect wavelengths of 490 nM.
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Animal Protocol |
Female CD-1 nu-/nu- mice (26-28 g) with Calu-6 cells[1]
1, 3.3, or 10 mg/kg SC; twice daily for 3 days, rest 4 days; for three cycles |
References |
Molecular Formula |
C18H19N7O2
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Molecular Weight |
365.39
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Exact Mass |
365.16
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Elemental Analysis |
C, 59.17; H, 5.24; N, 26.83; O, 8.76
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CAS # |
1234015-52-1
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Related CAS # |
Prexasertib dihydrochloride;1234015-54-3;Prexasertib dimesylate;1234015-58-7;Prexasertib Mesylate Hydrate;1234015-57-6;Prexasertib mesylate;1234015-55-4
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Appearance |
Solid powder
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SMILES |
COC1=C(C(=CC=C1)OCCCN)C2=CC(=NN2)NC3=NC=C(N=C3)C#N
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InChi Key |
DOTGPNHGTYJDEP-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C18H19N7O2/c1-26-14-4-2-5-15(27-7-3-6-19)18(14)13-8-16(25-24-13)23-17-11-21-12(9-20)10-22-17/h2,4-5,8,10-11H,3,6-7,19H2,1H3,(H2,22,23,24,25)
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Chemical Name |
5-[[5-[2-(3-aminopropoxy)-6-methoxyphenyl]-1H-pyrazol-3-yl]amino]pyrazine-2-carbonitrile
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Synonyms |
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HS Tariff Code |
2934.99.9001
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
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Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.7368 mL | 13.6840 mL | 27.3680 mL | |
5 mM | 0.5474 mL | 2.7368 mL | 5.4736 mL | |
10 mM | 0.2737 mL | 1.3684 mL | 2.7368 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT04095221 | Active Recruiting |
Drug: Prexasertib Drug: Irinotecan |
Desmoplastic Small Round Cell Tumor Rhabdomyosarcoma |
Memorial Sloan Kettering Cancer Center |
September 17, 2019 | Phase 1 Phase 2 |
NCT04023669 | Active Recruiting |
Drug: Prexasertib Drug: Gemcitabine |
Brain Cancer CNS Cancer |
St. Jude Children's Research Hospital |
August 8, 2019 | Phase 1 |
NCT02514603 | Completed | Drug: Prexasertib | Neoplasm | Eli Lilly and Company | October 2015 | Phase 1 |
NCT02778126 | Completed | Drug: [¹⁴C]Prexasertib Drug: Prexasertib |
Advanced Cancer | Eli Lilly and Company | September 22, 2016 | Phase 1 |
NCT03414047 | Completed | Drug: Prexasertib | Ovarian Cancer | Eli Lilly and Company | April 10, 2018 | Phase 2 |
Exposure to LY2606368 results in DNA damage during S-phase.Mol Cancer Ther.2015 Sep;14(9):2004-13. th> |
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The DNA damage effects of LY2606368 are dependent upon CDC25A and CDK2. LY2606368 causes chromosomal fragmentation.Mol Cancer Ther.2015 Sep;14(9):2004-13. td> |
LY2606368 causes DNA damage and growth inhibition in tumor xenografts.Mol Cancer Ther.2015 Sep;14(9):2004-13. td> |
LY2606368 induces replication stress and depletes the pool of available RPA2 for binding to DNA.Mol Cancer Ther.2015 Sep;14(9):2004-13. th> |
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Chk1 inhibitor LY2606368 can induce DNA damage and apoptosis, and can suppress cell proliferation in gastric cancer cells. LY2606368 can sensitize the anticancer effect of PARP inhibitor BMN673 in gastric cancer cells.Am J Cancer Res.2017 Mar 1;7(3):473-483. td> |
Chk1 inhibitor LY2606368 can suppress HR repair capacity. LY2606368 and BMN673 combination has synergistic anticancer effect in gastric cancer PDX model.Am J Cancer Res.2017 Mar 1;7(3):473-483. td> |