Prexasertib dihydrochloride (LY2606368 HCl) is a potent and selective ATP competitive inhibitor of the Chk1 protein kinase with IC50s of <1 nM and 8 nM for CHK1 and CHK2, respectively, and a Ki value of 0.9 nmol/L. 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. In a functional assay, LY2606368 potently abrogated the G2-M checkpoint activated by doxorubicin in p53-deficient HeLa cells with an EC50 of 9 nmol/L.
In vivo, LY2606368 was shown to inhibit the growth of primary tumors in an orthotopic SKOV3 ovarian cancer model, and significantly reduce the incidence of metastases and ascites accumulation. LY2606368 also demonstrated efficacy in an SW1990 orthotopic pancreatic cancer model resulting in a 92% inhibition of primary tumor growth and the elimination of metastases to the lymphnode, spleen, and intestine.
|Cell lines||HeLa cells|
|Preparation method||HeLa cells were plated onto T25 flasks and allowed to recover for 24 hours. LY2606368 was then added to give final concentrations of 33 or 100 nmol/L. In some experiments, 20μmol/L Z-VAD-FMK was included during the drug treatment. Cells were treated for 12 hours, and during the last 2 hours, colchicine was added to 1 μg/mL. Fixation of nuclei for metaphase spreads was done following the method of Bayani and Squire. Chromosome spreads were done. A 12-μL volume of cell suspension in 3:1 methanol/acetic acid fixative was dropped from a height of 3 cm onto dry glass slides or coverslips. The slides were then heated for 45 seconds on a 43°C metal block, before being removed to allow drying to complete at room temperature. Coverslips were mounted on slides with Vectashield Hard Set mounting medium with DAPI. Slides were examined with a Leica DMR fluorescence microscope and images were captured using a SPOT RT3 Slider camera.|
|Concentrations||33 or 100 nmol/L|
|Incubation time||12 h|
|Animal models||Female CD-1 nu-/nu- mice|
|Formulation||20% Captisol, pH4|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Chk1 inhibition potentiates the therapeutic efficacy of PARP inhibitor BMN673 in gastric cancer.
Yin Y, et al. Am J Cancer Res. 2017 Mar 1;7(3):473-483. PMID: 28401005.
Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer.
Hong D, et al. J Clin Oncol. 2016 May 20;34(15):1764-71. PMID: 27044938.
LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms.
King C, et al. Mol Cancer Ther. 2015 Sep;14(9):2004-13. PMID: 26141948.
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