Prexasertib HCl (LY2606368)

Catalog No.S7178

Prexasertib HCl (LY2606368) Chemical Structure

Molecular Weight(MW): 438.31

Prexasertib (LY2606368) is an ATP-competitive CHK1 inhibitor with a Ki value of 0.9 nmol/L. For CHK2 and RSK, its IC50 values are 8 nM and 9 nM respectively in cell-free assay.

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Cited by 1 Publication

1 Customer Review

  • EW8 and TC71 cells were treated with increasing doses of prexasertib for 6 hours. Cell lysates were then collected and blotted for p-CHK1-345.

    Mol Cancer Ther, 2018, 17(12):2676-2688. Prexasertib HCl (LY2606368) purchased from Selleck.

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Biological Activity

Description Prexasertib (LY2606368) is an ATP-competitive CHK1 inhibitor with a Ki value of 0.9 nmol/L. For CHK2 and RSK, its IC50 values are 8 nM and 9 nM respectively in cell-free assay.
Targets
Chk1 [1]
(Cell-free assay)
Chk2 [1]
(Cell-free assay)
RSK [1]
(Cell-free assay)
0.9 nM(Ki) 8 nM 9 nM
In vitro

In nonclinical studies, LY2606368 induced DNA damage as measured by replication catastrophe and increases in pH2A.X, a marker of double-stranded DNA breaks[1]. 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. LY2606368 was broadly antiproliferative with IC50 values typically <50 nmol/L in the most sensitive cell lines with a minority of cell lines showing considerable resistance with IC50's >1,000 nmol/L. LY2606368 requires CDC25A and CDK2 to cause DNA damage[2].

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
HeLa cells MY\GeY5kfGmxbjDhd5NigQ>? M4jESFM{KG:{IEGwNEBvdW:uL1y= MYe3JIhwfXK| NHjYcWJjgSB5IHjveZJ{NCCjIIP1ZpBweHWuYYTpc44hd2ZiY3XscJMhe3SjaX7l[EB{fHKxbnfsfUBnd3JiRGPCJIJ6KGKxdHigWHVPTUxiYX7kJJBJOkG[ Moi3NlYyPDF7NEi=
U-2 OS cells M3LQUGZ2dmO2aX;uJIF{e2G7 MVq0JI5ud2xxTB?= MXuyOEBp M2XE[IEhdGG{Z3Wgd4hq\nRiaX6gZ4VtdC2leXPs[UBxd3C3bHH0bY9veyCocn;tJGcyKGGwZDDHNwKBm01idH:gV{1xcGG|ZTD3bZRpKGGwIHHjZ49ueGGwaXXkJIlv\HWldHnvckBw\iCKMlHYJJBpd3OyaH;yfYxifGmxbj6= MXmyOlE1OTl2OB?=
CCRF-CEM parental cells M2jGfWZ2dmO2aX;uJIF{e2G7 NWLO[XJpOTBibl2= NX\ETFRiPCCq MmHDbY5lfWOnZDDTUGZPOTFiYnnu[Ilv\yC2bzDjbJJwdWG2aX6gZY5lKGmwY4LlZZNm\CC2aHWgZ4hzd22jdHnuJIJqdmSrbnegc4YhS0SFNEW= NGPIRVgzQTN7NUC2NS=>
SLFN11-del cells MoPLSpVv[3Srb36gZZN{[Xl? NFHYO2wyOCCwTR?= NW\lOoNxPCCq NIPxSWlqdmS3Y3XkJHNNTk5zMTDibY5lcW6pIITvJINpem:vYYTpckBidmRiaX7jdoVie2WmIITo[UBkcHKxbXH0bY4h[mmwZHnu[{Bw\iCFRFO0OS=> MnrXNlk{QTVyNkG=
K562-WT M{f0R2Z2dmO2aX;uJIF{e2G7 MVuxNFAhdk1? NYnIOW44OiCq NHPUWWJUVE[QMUGsJGNFSzR3IHHu[EBRS06DIIfldoUh\W6{aXPo[YQhd25ibnHzZ4VvfCCGTlG= MXqyPVM6PTB4MR?=
K562-E669Q MoLYSpVv[3Srb36gZZN{[Xl? M{HvSVExOCCwTR?= M4HRO|IhcA>? NWrMU5ZqW0yITkGxMEBETEN2NTDhcoQhWEOQQTD3[ZJmKGWwcnnjbIVlKG:wIH7hd4NmdnRiRF7B MUWyPVM6PTB4MR?=
CCRF-CEM parental cells NUTwNGxkTnWwY4Tpc44h[XO|YYm= NWrGXo1GOTByIH7N M4XKNFIhcA>? MUDTUGZPOTFuIFPER|Q2KGGwZDDQR25CKHencnWg[Y5zcWOqZXSgc44hdmG|Y3XueEBFVkF? NW\RT4FkOjl|OUWwOlE>
HCT-116 cells NEnE[lhHfW6ldHnvckBie3OjeR?= NHr6TnIyOOLCr3ThfZM> NWTKe25FcW6qaXLpeIVlKGKxdHigSmFPS0R{IIXibZF2cXSrbnH0bY9vKGGwZDDpcoNz\WG|ZXSgVoFlPTFibHX2[Yx{NCC|aXfubYZq[2GwdHz5JIlv[3KnYYPl[EB{\W6|aYTpeol1gSCxZjDIR3QuOTF4IHPlcIx{KHSxIF[xNC=> MmXsN|A1Ozl3Nke=
U937 cells MWnGeY5kfGmxbjDhd5NigQ>? MorLN-KBkW6P M4C2NoVvcGGwY3XkJJRp\SCleYTveI95cWOrdImgc4YhS1C[LUO1NUBifCCub4egcoFvd22xbHHyJINwdmOnboTyZZRqd26| M37sUlMxQDN5NkSz

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
CHK1 / p-CHK1(Ser345) / γH2AX / Cleaved caspase3 ; 

PubMed: 28401005     


E, F. Western blot analyses of AGS and MKN1 cells treated with LY2606368 for 24 hours. Endogenous Chk1, γ-H2AX, cleaved caspase3, and p-Chk1 (Ser345) were detected using their respective antibodies as shown left to each panel.

pS6 (S235/236) / pS6 (S240/244); 

PubMed: 28490518     


Immunoblot analysis of H69 and H69/CR cells before and after treatment with LY2606368 (24 hours; 100 nmol/L). The basal expression level of pS6 S240/244 and pS6 S235/236 was lower in nontreated H69 cells than in nontreated H69/CR cells, and this was further abrogated by treatment with LY2606368. Actin was used as a loading control.

28401005 28490518
Immunofluorescence
SLFN11 / CDC45 / EdU; 

PubMed: 29395061     


Immunofluorescence analysis for DNA replication (EdU) (purple), chromatin-bound SLFN11 (green), CDC45 (red) and DAPI (blue). CCRF-CEM parental and SLFN11-del cells were treated for 4 hours with CHK1 inhibitor (CHK1i, LY2606368, 10 nM]. EdU was added 30 min before cell collection.

29395061
Growth inhibition assay
Cell viability; 

PubMed: 28401005     


Graphical presentation of % cell viability of AGS and MKN1 cells measured 3 days after treatment with LY2606368.

IC50; 

PubMed: 28490518     


Cell viability in response to treatment with LY2606368 in a panel of human SCLC (hSCLC) cell lines (blue bars), GEMM-derived SCLC cell lines (green bars), a PDX-derived cell line (yellow bar), a large-cell neuroendocrine carcinoma (LCNEC) cell line (black bar), and NSCLC cell lines (red bars). 

28401005 28490518
In vivo LY2606368 inhibited tumor growth in cancer xenografts as monotherapy and in combination with other agents[1]. In an orthotopic SKOV3 ovarian cancer model, LY2606368 was shown to inhibit the growth of primary tumors 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[3].

Protocol

Cell Research:

[2]

+ Expand
  • Cell lines: HeLa cells
  • Concentrations: 33 or 100 nmol/L
  • Incubation Time: 12 h
  • 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.


    (Only for Reference)
Animal Research:

[2]

+ Expand
  • Animal Models: Female CD-1 nu-/nu- mice
  • Formulation: 20% Captisol, pH4
  • Dosages: 15 mg/kg
  • Administration: s.c.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 2 mg/mL (4.56 mM)
Water Insoluble
Ethanol Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 438.31
Formula

C18H19N7O2.2HCl

CAS No. 1234015-54-3
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04095221 Recruiting Drug: Prexasertib|Drug: Irinotecan|Drug: Temozolomide Desmoplastic Small Round Cell Tumor|Rhabdomyosarcoma Memorial Sloan Kettering Cancer Center September 17 2019 Phase 1|Phase 2
NCT03495323 Recruiting Drug: LY3300054|Drug: Prexasertib Cancer Dana-Farber Cancer Institute|Eli Lilly and Company May 16 2018 Phase 1
NCT03414047 Active not recruiting Drug: Prexasertib Ovarian Cancer Eli Lilly and Company April 10 2018 Phase 2
NCT03057145 Recruiting Drug: Prexasertib|Drug: Olaparib Solid Tumor Khanh Do|Eli Lilly and Company|AstraZeneca|Dana-Farber Cancer Institute March 10 2017 Phase 1

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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Frequently Asked Questions

  • Question 1:

    Would you please suggest a suitable vehicle to dissolve Prexasertib HCl (LY2606368) for in vivo use?

  • Answer:

    You can dissolve S7178 in a vehicle: 5% DMSO+40%PEG 300+5%Tween80+ddH2O for in vivo use in mice (i.p.). This stock concentration reahces 10mg/ml, and can be prepared for work solution as 0.5mg/ml, stable for no longer than 30min.

  • Question 2:

    What is the solubility of LY2606368 in 20% Captisol?

  • Answer:

    S7178 in 20% Captisol is a suspension, which is fine for oral gavage. You can dissolve it in this vehicle to the concentration you need as long as the suspension is homogeneous.

Chk Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID