Prexasertib (LY2606368) is a substrate ATP competitively selective inhibitor of CHK1 and CHK2 with IC50 values of <1 nM and 8 nM against CHK1 and CHK2, respectively. LY2606368 treatment led to TUNEL and pH2AXy positive double-stranded DNA breaks in cells in S phase. LY2606368 effectively cancelled the G2-M checkpoint activated by Doxorubicin in P53-deficient HeLa cells with EC50 of 9 nM. LY2606368 can play an antiproliferative role in a wide range of cells, with IC50s < 50 nM in most sensitive cell lines. Only a few cell lines were resistant to LY2606368, IC50s > 1000 nM.
In vivo studies, LY2606368 can effectively inhibit tumor growth in tumor xenograft model and exert anti-tumor activity. In the SKOV3 ovarian cancer model, LY2606368 inhibited the growth of primary tumor and significantly reduced the rate of metastasis and ascites accumulation. In SW1990 model of pancreatic carcinoma in situ, LY2606368 inhibited the growth of 92% of the primary tumor and prevented its metastasis to lymph node tuberculosis, 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 Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
|Solubility||DMSO 2 mg/mL|
|Related Checkpoint Products|
WAY-239320 is a Chk1 inhibitor
Prexasertib dimesylate (LY2606368 dimesylate) is a selective, ATP-competitive second-generation checkpoint kinase 1 (CHK1) inhibitor with a Ki of 0.9 nM and an IC50 of <1 nM.
Prexasertib (LY2606368) is a selective, ATP-competitive second-generation checkpoint kinase 1 (CHK1) inhibitor with a Ki of 0.9 nM and an IC50 of <1 nM.
GDC-0575 dihydrochloride (ARRY-575 dihydrochloride) is an orally bioavailable CHK1 inhibitor, with an IC50 of 1.2 nM, and has antitumor activity.
CCT244747 is a potent, orally bioavailable and highly selective CHK1 inhibitor, with an IC50 of 7.7 nM; CCT244747 also abrogates G2 checkpoint with an IC50 of 29 nM.
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