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[CAS NO. 1234015-54-3] Prexasertibdihydrochloride
| Ships within | Stock | Price | Qty | Total |
Please click "REQUEST A QUOTE" button if there is no stock, or you need other sizes or custom synthesis.
| Catalog: | HY-18174A |
| Brand: | MCE |
| CAS: | 1234015-54-3 |
Overview
| MDL | - |
|---|---|
| Molecular Weight | 438.31 |
| Molecular Formula | C18H21Cl2N7O2 |
| SMILES | NCCCOC(C=CC=C1OC)=C1C2=CC(NC3=NC=C(C#N)N=C3)=NN2.[H]Cl.[H]Cl |
16 Publications Citing Use of MCE
- [1]Nat Commun. 2019 Aug 2;10(1):3485.
- [2]Thorax. 2021 Jul 5;thoraxjnl-2021-217377.
- [3]Oncogene. 2022 Oct 12.
- [4]Cell Biol Toxicol. 2021 Sep 14.
- [5]Cancers (Basel). 2021 Aug 20;13(16):4200.
- [6]Cancers. 2020 Aug 26;12(9):2426.
- [7]Cancers. 2020 Jun 29;12(7):1726.
- [8]Br J Cancer. 2021 Mar 26.
- [9]Mol Cancer Res. 2019 Oct;17(10):2102-2114.
- [10]Sci Rep. 2021 Feb 4;11(1):3176.
- [11]Universität Hamburg. Elektronische Dissertationen und Habilitationen. 2022 Aug.
- [12]bioRxiv. January 04, 2022.
- [13]Patent. US20210353605A1.
- [14]bioRxiv. September 10, 2021.
- [15]Research Square Preprint. 2021 May.
- [16]Methods Mol Biol. 2018;1711:351-398.
Summary
Prexasertib dihydrochloride (LY2606368 dihydrochloride) is a selective, ATP-competitive second-generation checkpoint kinase 1 (CHK1) inhibitor with a K i of 0.9 nM and an IC 50 of <1 nM. Prexasertib dihydrochloride inhibits CHK2 (IC 50 =8 nM) and RSK1 (IC 50 =9 nM). Prexasertib dihydrochloride causes double-stranded DNA breakage and replication catastrophe resulting in apoptosis . Prexasertib dihydrochloride shows potent anti-tumor activity [1] [2] .
IC50 & Target
|
Chk1 0.9 nM (Ki) |
Chk1 <1 nM (IC 50 ) |
Chk2 8 nM (IC 50 ) |
In Vitro
Prexasertib dihydrochloride (LY2606368 dihydrochloride) inhibits MELK (IC
50
=38 nM), SIK (IC
50
=42 nM), BRSK2 (IC
50
=48 nM), ARK5 (IC
50
=64 nM). LY2606368 requires CDC25A and CDK2 to cause DNA damage
[1]
.
Prexasertib dihydrochloride (33, 100 nM; for 7 hours) results in DNA damage during S-phase in HeLa cells
[1]
.
Prexasertib dihydrochloride (8-250 nM; pre-treated for 15 minutes) inhibits CHK1 autophosphorylation (S296) and CHK2 autophosphorylation (S516) in HT-29 cells
[1]
.
Prexasertib dihydrochloride (4 nM; 24 hours) 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
[1]
.
Prexasertib dihydrochloride (33 nM; for 12 hours) causes chromosomal fragmentation in HeLa cells. Prexasertib (100 nM; 0.5 to 9 hours) induces replication stress and depletes the pool of available RPA2 for binding to DNA
[1]
.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Cell Cycle Analysis [1]
| Cell Line: | HeLa cells |
| Concentration: | 33, 100 nM |
| Incubation Time: | For 7 hours |
| Result: | Had an IC 50 of 37 nM and resulted in the G2-M population received DNA damage during S-phase but continued to progress through the cell cycle into an early mitosis. |
Western Blot Analysis [1]
| Cell Line: | HT-29 cells |
| Concentration: | 8, 16, 31, 63, 125, 250 nM |
| Incubation Time: | Pre-treated for 15 minutes |
| Result: | Inhibited CHK1 autophosphorylation (S296) and CHK2 autophosphorylation (S516) (IC 50 of less than 31 nM) in HT-29 cells. |
In Vivo
Prexasertib dihydrochloride (LY2606368 dihydrochloride; 1-10 mg/kg; SC; twice daily for 3 days, rest 4 days; for three cycles) causes growth inhibition in tumor xenografts
[1]
.
Prexasertib dihydrochloride (15 mg/kg; SC) causes CHK1 inhibition in the blood and the phosphorylation of both H2AX (S139) and RPA2 (S4/S8)
[1]
.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
| Animal Model: | Female CD-1 nu-/nu- mice (26-28 g) with Calu-6 cells [1] |
| Dosage: | 1, 3.3, or 10 mg/kg |
| Administration: | SC; twice daily for 3 days, rest 4 days; for three cycles |
| Result: | Caused statistically significant tumor growth inhibition (up to 72.3%). |
| Animal Model: | Female CD-1 nu-/nu- mice (26-28 g) with Calu-6 cells [1] |
| Dosage: | 15 mg/kg (Pharmacokinetic Analysis) |
| Administration: | SC (200 μL) |
| Result: |
CHK1 was 7 ng/mL at 12 hours and 3 ng/mL by 24 hours in plasma exposures.
Phosphorylation of both H2AX (S139) and RPA2 (S4/S8) was detectable at 4 hours, showing the rapid occurrence of DNA damage. |
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date | Phase |
|---|---|---|---|---|
| NCT03414047 | Eli Lilly and Company |
Ovarian Cancer
|
April 10, 2018 | Phase 2 |
| NCT04095221 | Memorial Sloan Kettering Cancer Center |
Desmoplastic Small Round Cell Tumor|Rhabdomyosarcoma
|
September 17, 2019 | Phase 1|Phase 2 |
| NCT02778126 | Eli Lilly and Company |
Advanced Cancer
|
September 22, 2016 | Phase 1 |
| NCT03495323 | Dana-Farber Cancer Institute|Eli Lilly and Company |
Cancer
|
May 16, 2018 | Phase 1 |
| NCT04023669 | St. Jude Children´s Research Hospital|Eli Lilly and Company |
Brain Tumor|Brain Tumor, Recurrent|Brain Tumor, Refractory|Brain Tumor, Pediatric|Medulloblastoma|Medulloblastoma Recurrent|Medulloblastoma, Non-WNT+Non-SHH|Medulloblastoma, Non-WNT+Non-SHH, Group 3|Medulloblastoma, Non-WNT+Non-SHH, Group 4|Brain Cancer|CNS Cancer|CNS Tumor|CNS Neoplasm
|
August 8, 2019 | Phase 1 |
| NCT02860780 | Eli Lilly and Company |
Advanced Cancer|Metastatic Cancer|Colorectal Cancer|Non-small Cell Lung Cancer
|
August 10, 2016 | Phase 1 |
| NCT02514603 | Eli Lilly and Company |
Neoplasm
|
October 2015 | Phase 1 |
| NCT02873975 | Dana-Farber Cancer Institute |
Advanced Cancers
|
October 12, 2016 | Phase 2 |
| NCT04032080 | Baylor Research Institute|Eli Lilly and Company |
Triple Negative Breast Cancer
|
September 5, 2019 | Phase 2 |
| NCT02735980 | Eli Lilly and Company |
Small Cell Lung Cancer
|
May 11, 2016 | Phase 2 |
| NCT02203513 | National Cancer Institute (NCI)|National Institutes of Health Clinical Center (CC) |
Ovarian Cancer|Breast Cancer|Prostate Cancer
|
January 20, 2015 | Phase 2 |
| NCT02555644 | Eli Lilly and Company |
Head and Neck Neoplasms
|
February 24, 2016 | Phase 1 |
| NCT02808650 | Children´s Oncology Group|National Cancer Institute (NCI) |
Childhood Solid Neoplasm|Recurrent Malignant Solid Neoplasm|Recurrent Primary Central Nervous System Neoplasm|Refractory Malignant Solid Neoplasm|Refractory Primary Central Nervous System Neoplasm
|
February 27, 2017 | Phase 1 |
| NCT02649764 | M.D. Anderson Cancer Center|National Cancer Institute (NCI) |
Chronic Myelomonocytic Leukemia|Recurrent Acute Myeloid Leukemia|Recurrent High Risk Myelodysplastic Syndrome|Refractory Acute Myeloid Leukemia|Refractory High Risk Myelodysplastic Syndrome
|
May 4, 2016 | Phase 1 |
| NCT03057145 | Geoffrey Shapiro, MD, PhD|Eli Lilly and Company|AstraZeneca|Dana-Farber Cancer Institute |
Solid Tumor
|
March 10, 2017 | Phase 1 |
| NCT02124148 | Eli Lilly and Company |
Neoplasm Metastasis|Colorectal Neoplasms|Breast Cancer
|
June 18, 2014 | Phase 1 |
| NCT01115790 | Eli Lilly and Company |
Advanced Cancer|Squamous Cell Carcinoma|Carcinoma, Squamous Cell of Head and Neck|Lung Squamous Cell Carcinoma Stage IV|Anal Squamous Cell Carcinoma|Carcinoma, Non-Small-Cell Lung
|
February 2010 | Phase 1 |
| NCT03735446 | Dana-Farber Cancer Institute|Eli Lilly and Company |
Acute Myeloid Leukemia|Myelodysplastic Syndromes
|
January 18, 2019 | Phase 1 |
Appearance
Solid
Shipping
Room temperature in continental US; may vary elsewhere.
Storage
4°C, sealed storage, away from moisture
* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)
Solvent & Solubility
DMSO : 8 mg/mL ( 18.25 mM ; Need ultrasonic)
H 2 O : 1 mg/mL ( 2.28 mM ; ultrasonic and warming and heat to 80°C)
Stock Solutions
| Concentration Solvent Mass | 1 mg | 5 mg | 10 mg |
|---|
| 1 mM | 2.2815 mL | 11.4075 mL | 22.8149 mL |
| 5 mM | 0.4563 mL | 2.2815 mL | 4.5630 mL |
| 10 mM | 0.2281 mL | 1.1407 mL | 2.2815 mL |
-
1.
-
2.
Add each solvent one by one: 10% DMSO >> 90% (20% SBE-β-CD in saline)
Solubility: ≥ 0.8 mg/mL (1.83 mM); Clear solution
References
- [1] King C, et al. LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms. Mol Cancer Ther. 2015 Sep;14(9):2004-1
- [2] Yin Y, 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.
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