LY2606368 (Synonyms: Prexasertib) |
| رقم الكتالوجGC15663 |
LY2606368 (LY2606368) هو مثبط انتقائي من الجيل الثاني لنقاط التفتيش كيناز 1 (CHK1) منافس لـ ATP مع Ki 0.9 نانومتر و IC50 <1 نانومتر. LY2606368 يثبط CHK2 (IC50 = 8 نانومتر) و RSK1 (IC50 = 9 نانومتر). يتسبب LY2606368 في كسر الحمض النووي مزدوج الشريطة وكارثة النسخ المتماثل مما يؤدي إلى موت الخلايا المبرمج. يظهر LY2606368 نشاطًا قويًا مضادًا للورم.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1234015-52-1
Sample solution is provided at 25 µL, 10mM.
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LY2606368, an ATP-competitive CHK1 inhibitor, is currently in the clinical stage with a Ki of 0.9 nM and an IC50 of <1 nM. LY2606368 inhibits CHK2 (IC50=8 nM) and RSK1 (IC50=9 nM)[2].
Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe[1].LY2606368 triggered S-phase DNA damage, such as pH2AX (S139) and TUNEL positive staining cells significantly increased in S-phase cells. LY2606368 also requires CDC25A and CDK2 to trigger DNA damage. In addition, LY2606368 causes replication catastrophe[1]. In primary patient-derived osteosarcoma cells, LY2606368 alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double-stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations[3]. To investigate the combined effect of the Chk1 inhibitor LY2606368and antitumor drugs (GEM and S 1) on pancreatic cancer cell line SUIT 2. Acombination of LY2606368 and GS showed effective induction of apoptosis[4]. HGSOC cell lines were also sensitive to LY2606368, associated with induction of DNA damage and replication stress. LY2606368 also sensitized these cell lines to PARP inhibition and compromised both HR repair and replication fork stability[5]. BRCAwt HGSOC develops resistance to LY2606368 monotherapy via a prolonged G2 delay induced by lower CDK1/CyclinB1 activity, thus preventing cells from mitotic catastrophe and cell death[6]. PLK1 or CHEK1 inhibitors (BI-2536 or LY2606368) were found to exert a superior anticancer effect against cell lines at low nanomolar concentrations and induce cell-cycle arrest[7].
Up to 72.3% inhibition of tumor growth was observed in the three doses of LY2606368 tested, and mice lost no more than 3% of their body weight, indicating that LY2606368 was well tolerated in any treatment group. In addition, tumor regrowth was slow in the highest dose group during the 28-day recovery period, indicating a durable tumor response to LY2606368[1].
References:
[1]: King C, Diaz HB,et,al. Barda D, Marshall MS. LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms. Mol Cancer Ther. 2015 Sep;14(9):2004-13. doi: 10.1158/1535-7163.MCT-14-1037. Epub 2015 Jul 3. PMID: 26141948.
[2]: Yin Y, Shen Q, et,al. Chk1 inhibition potentiates the therapeutic efficacy of PARP inhibitor BMN673 in gastric cancer. Am J Cancer Res. 2017 Mar 1;7(3):473-483. PMID: 28401005; PMCID: PMC5385637.
[3]: Heidler CL, Roth EK, et,al. Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient-derived osteosarcoma cells and synergizes with cisplatin and talazoparib. Int J Cancer. 2020 Aug 15;147(4):1059-1070. doi: 10.1002/ijc.32814. Epub 2019 Dec 19. PMID: 31782150; PMCID: PMC7384073.
[4]: Morimoto Y, Takada K, et,al. Prexasertib increases the sensitivity of pancreatic cancer cells to gemcitabine and S?1. Oncol Rep. 2020 Feb;43(2):689-699. doi: 10.3892/or.2019.7421. Epub 2019 Nov 28. PMID: 31789403.
[5]: Parmar K, Kochupurakkal BS, et,al. The CHK1 Inhibitor Prexasertib Exhibits Monotherapy Activity in High-Grade Serous Ovarian Cancer Models and Sensitizes to PARP Inhibition. Clin Cancer Res. 2019 Oct 15;25(20):6127-6140. doi: 10.1158/1078-0432.CCR-19-0448. Epub 2019 Aug 13. PMID: 31409614; PMCID: PMC6801076.
[6]: Nair J, Huang TT, et,al. Resistance to the CHK1 inhibitor prexasertib involves functionally distinct CHK1 activities in BRCA wild-type ovarian cancer. Oncogene. 2020 Aug;39(33):5520-5535. doi: 10.1038/s41388-020-1383-4. Epub 2020 Jul 9. PMID: 32647134; PMCID: PMC7426265.
[7]: Yoshida K, Yokoi A, et,al. Aberrant Activation of Cell-Cycle-Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma. Clin Cancer Res. 2022 May 13;28(10):2147-2159. doi: 10.1158/1078-0432.CCR-22-0100. PMID: 35302600.
| Kinase experiment [1]: | |
|
Preparation Method |
Purified CHK1 was incubated with LY2606368 and substrate was added to detect whether LY2606368 was inhibited. |
|
Reaction Conditions |
10-6-10nM LY2606368 |
|
Applications |
LY2606368 is an ATP-competitive protein kinase inhibitor with a Ki of 0.9 nmol/L against purified CHK1. |
| Cell experiment [2]: | |
|
Cell lines |
HeLa cells |
|
Preparation Method |
Cells were treated with LY2606368 for 7 hours and stained for evidence of DNA DSB using both TUNEL and an antibody for H2AX phosphorylated on serine 139. |
|
Reaction Conditions |
33 nmol/L LY2606368 for 7 hours |
|
Applications |
LY2606368 triggered S-phase DNA damage, such as pH2AX (S139) and TUNEL positive staining cells significantly increased in S-phase cells. LY2606368 also requires CDC25A and CDK2 to trigger DNA damage. In addition, LY2606368 causes replication catastrophe. |
| Animal experiment [3]: | |
|
Animal models |
Female CD-1nu-/nu mice carrying CALU-6 tumors (26-28 g) |
|
Preparation Method |
Vehicle consisting of 20% Captisol (CyDex Inc) pH4 or LY2606368 was administered by subcutaneous injection in a volume of 200 ml(10 mmol/L). 4,8, 12, 24, and 48 hours after drug administration, blood for plasma drug exposure was extracted |
|
Dosage form |
1, 3.3, or 10 mg/kg LY2606368 twice daily for 2 days |
|
Applications |
Up to 72.3% inhibition of tumor growth was observed in the three doses of LY2606368 tested, and mice lost no more than 3% of their body weight, indicating that LY2606368 was well tolerated in any treatment group. In addition, tumor regrowth was slow in the highest dose group during the 28-day recovery period, indicating a durable tumor response to LY2606368. |
|
References: [1]. King C, Diaz HB, et,al. LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms. Mol Cancer Ther. 2015 Sep;14(9):2004-13. doi: 10.1158/1535-7163.MCT-14-1037. Epub 2015 Jul 3. PMID: 26141948. |
|
| Cas No. | 1234015-52-1 | SDF | |
| المرادفات | Prexasertib | ||
| Chemical Name | (Z)-5-((5-(2-(3-aminopropoxy)-6-methoxyphenyl)-1H-pyrazol-3(2H)-ylidene)amino)pyrazine-2-carbonitrile | ||
| Formula | C18H19N7O2 | M.Wt | 365.39 |
| الذوبان | <0.73mg/mL in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
1 mg | 5 mg | 10 mg |
| 1 mM | 2.7368 mL | 13.684 mL | 27.368 mL |
| 5 mM | 0.5474 mL | 2.7368 mL | 5.4736 mL |
| 10 mM | 0.2737 mL | 1.3684 mL | 2.7368 mL |
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
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3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 12 reference(s) in Google Scholar.)
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