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Prexasertib mesylate (also known as LY2606368 mesylate) is a novel, potent, selective and ATP competitive inhibitor of the CHK1 (checkpoint kinase 1) protein kinase with potential anticancer activity. Its IC50 values for CHK1 and CHK2 are less than 1 nM and 8 nM, respectively. One multipurpose protein kinase that is essential to the cellular response to DNA damage is CHK1, which also regulates the quantity of replication forks that are actively replicating. The function of CHK1 in establishing DNA damage checkpoints in the cell cycle has led to the current investigation of CHK1 inhibitors as chemopotentiating agents. When taken by itself, prexasertib breaks double-stranded DNA and eliminates the DNA damage checkpoints' defense systems. Prexasertib works by inhibiting CHK1, which raises CDC25A activation of CDK2, increasing the number of replication forks while decreasing their stability. TUNEL and pH2AX-positive double-stranded DNA breaks quickly manifest in the S-phase cell population following Prexasertib treatment. Ex vivo tumor models demonstrate comparable responses to ixasertib, including marked inhibition of tumor growth. In summary, 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) mesylate inhibits BRSK2 (IC50=48 nM), ARK5 (IC50=64 nM), SIK (IC50=42 nM), and MELK (IC50=38 nM). In order to damage DNA, prexasertib mesylate needs CDK2 and CDC25A[1].
Prexasertib mesylate (33, 100 nM; for 7 hours) for 7 hours causes damage to DNA during the S-phase in HeLa cells[1]. Prexasertib mesylate (8-250 nM; pre-treated for 15 minutes) inhibits the autophosphorylation of CHK1 (S296) and CHK2 (S516)[1]. Prexasertib mesylate (4 nM; 24 hours) induces H2AX phosphorylation and causes a significant shift in cell cycle populations from G1 and G2-M to S-phase in U-2 OS cells[1]. Prexasertib mesylate (33 nM; for 12 hours) chromosomal fragmentation in HeLa cells. Prexasertib mesylate (100 nM; 0.5 to 9 hours) reduces the amount of RPA2 that is available to bind to DNA and causes replication stress[1]. |
| ln Vivo |
Prexasertib mesylate (1-10 mg/kg; SC; twice daily for 3 days, rest 4 days; for three cycles) inhibits the growth of tumor xenografts[1].
Prexasertib mesylate (15 mg/kg; SC) causes the phosphorylation of RPA2 (S4/S8) and H2AX (S139) in addition to 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 |
On T25 flasks, HeLa cells were plated, and they were given 24 hours to heal. The final concentrations of 33 or 100 nmol/L were then obtained by adding LY2606368. In certain studies, the drug treatment included 20μmol/L Z-VAD-FMK. After the 12-hour treatment, 1 μg/mL of colchicine was added during the final two hours of treatment. Using the methodology of Bayani and Squire, nuclei were fixed for metaphase spreads. Chromosome spreads were done. A 12-μL volume of cell suspension in a 3:1 methanol/acetic acid fixative was dropped onto coverslips or dry glass slides from a height of 3 cm. After that, the slides were heated for 45 seconds on a metal block set at 43°C. After that, they were taken out to finish drying at room temperature. Using DAPI, coverslips were adhered to slides using Vectashield Hard Set mounting medium. A Leica DMR fluorescent microscope was used to examine the slides, and a SPOT RT3 Slider camera was used to take pictures.
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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 |
C19H23N7O5S
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| Molecular Weight |
461.50
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| Exact Mass |
461.14813803
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| Elemental Analysis |
C, 49.45; H, 5.02; N, 21.25; O, 17.33; S, 6.95
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| CAS # |
1234015-55-4
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| Related CAS # |
Prexasertib;1234015-52-1;Prexasertib dihydrochloride;1234015-54-3;Prexasertib dimesylate;1234015-58-7;Prexasertib Mesylate Hydrate;1234015-57-6
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| Appearance |
Yellow solid powder
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| SMILES |
COC1=C(C(=CC=C1)OCCCN)C2=CC(=NN2)NC3=NC=C(N=C3)C#N.CS(=O)(=O)O
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| InChi Key |
WGCKOJKXQKKLQW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H19N7O2.CH4O3S/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;1-5(2,3)4/h2,4-5,8,10-11H,3,6-7,19H2,1H3,(H2,22,23,24,25);1H3,(H,2,3,4)
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| Chemical Name |
5-[[5-[2-(3-aminopropoxy)-6-methoxyphenyl]-1H-pyrazol-3-yl]amino]pyrazine-2-carbonitrile;methanesulfonic acid
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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 | 2.1668 mL | 10.8342 mL | 21.6685 mL | |
| 5 mM | 0.4334 mL | 2.1668 mL | 4.3337 mL | |
| 10 mM | 0.2167 mL | 1.0834 mL | 2.1668 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 |
| NCT02808650 | Completed | Other: Pharmacological Study Drug: Prexasertib |
Childhood Solid Neoplasm Recurrent Malignant Solid Neoplasm |
Children's Oncology Group | February 27, 2017 | Phase 1 |
 Exposure to LY2606368 results in DNA damage during S-phase.Mol Cancer Ther.2015 Sep;14(9):2004-13. |
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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. |
LY2606368 causes DNA damage and growth inhibition in tumor xenografts.Mol Cancer Ther.2015 Sep;14(9):2004-13. |
 LY2606368 induces replication stress and depletes the pool of available RPA2 for binding to DNA.Mol Cancer Ther.2015 Sep;14(9):2004-13. |
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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. |
 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. |
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