[CAS NO. 1234015-54-3] Prexasertibdihydrochloride

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PRODUCTS SPECIFICATIONS [1234015-54-3]

Catalog

HY-18174A

Brand

MCE

CAS

1234015-54-3

DESCRIPTION [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

For research use only. We do not sell to patients.

16 Publications Citing Use of MCE

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

In Vitro:

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)

Preparing
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

* Please refer to the solubility information to select the appropriate solvent.

In Vivo:

1.

Add each solvent one by one: 10% DMSO >> 40% PEG300 >> 5% Tween-80 >> 45% saline

Solubility: ≥ 0.8 mg/mL (1.83 mM); Clear solution
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

* All of the co-solvents are available by MCE.