LY2603618

Catalog No.S2626

LY2603618 is a selective Chk1 inhibitor with potential anti-tumor activity in a cell-free assay. Phase 2.

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LY2603618 Chemical Structure

LY2603618 Chemical Structure
Molecular Weight: 436.3

Validation & Quality Control

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Quality Control & MSDS

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Product Description

Biological Activity

Description LY2603618 is a selective Chk1 inhibitor with potential anti-tumor activity in a cell-free assay. Phase 2.
Targets Chk1 [1]
(Cell-free assay)
In vitro Chk1 is an ATP-dependent serine-threonine kinase and a key component in the DNA replication-monitoring checkpoint system activated by double-stranded breaks (DSBs). Chk1 contributes to all currently defined cell cycle checkpoints, including G1/S, intra-S-phase, G2/M, and the mitotic spindle checkpoint. By inhibiting the activity of chk1, LY2603618 prevents the repair of DNA caused by DNA-damaging agents, thus potentiating the antitumor efficacies of various chemotherapeutic agents. However, preclinical data involving LY2603618 has not been published until now. [1] Inhibition of Chk1 is predicted to enhance the effects of antimetabolites, such as gemcitabine. [2] LY2603618 treatment impairs DNA synthesis, increases DNA damage (via mitotic defects), induces apoptosis, and has synergistic activity with pemetrexed, especially in p53 mutant tumor cells. [3]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
BT474M4TadGtqdmG|ZTDhd5NigQ>?MUOxJO69VQ>?NG\iWZFFVVORMWjpcohq[mm2czDQMWNJUzFibHX2[Yx{NWfs[5l5OjN7MUezO|g>
MCF7NFXkXpJMcW6jc3WgZZN{[Xl?NGfTUW0yKM7:TR?=NV7EbGlwTE2VTx?=MYHpcohq[mm2czDQMWNJUzFibHX2[Yx{M2TlbVI{QTF5M{e4
HelaNH61TVVMcW6jc3WgZZN{[Xl?M{jCN|M{ODBibl2=NUDUT3BKTE2VTx?=M1HLcolvcGmkaYTzJGNpczFiYXP0bZZqfHl?M1TsR|I1OTF2MUK0
Calu6MUPLbY5ie2ViYYPzZZk>MWizN|AxKG6PMXrEUXNQM{fJcYlvcGmkaYTzJGNpczFiYXP0bZZqfHl?NGXYd4kzPDFzNEGyOC=>
A549NUHPXGk5TnWwY4Tpc44h[XO|YYm=MVv+NVAh|ryPMlHWSG1UVw>?M3;KeYlv\HWlZYOgZ4VtdCCleXPs[UBienKnc4S=NXPoUpQ3OjR7MkiyNFU>
H1299M2fYZWZ2dmO2aX;uJIF{e2G7MlS5glExKM7:TR?=MWXEUXNQM{TBeIlv\HWlZYOgZ4VtdCCleXPs[UBienKnc4S=MYeyOFkzQDJyNR?=
A549MlfQSpVv[3Srb36gZZN{[Xl?NEjh[oZ,OjBizszNMX\EUXNQNX\aVpdF[WO2aY\heIV{KESQQTDkZY1i\2Vic3Xud49zKGurbnHz[ZM>NVXhOZRlOjR7MkiyNFU>
H1299MmTUSpVv[3Srb36gZZN{[Xl?MVX+NlAh|ryPNEf0fZZFVVORMlXkZYN1cX[jdHXzJGRPSSCmYX3h[4Uhe2Wwc3;yJItqdmG|ZYO=MXeyOFkzQDJyNR?=
A549NXS5WHE{SXCxcITvd4l{KGG|c3H5Ml3OglIxKM7:TR?=NHnGdYFFVVORMmLGbY5lfWOnczDhdI9xfG:|aYO=M2ewT|I1QTJ6MkC1
H1299NV;Yd4FQSXCxcITvd4l{KGG|c3H5M1ywc54zOCEQvF2=M4j1RWROW09?NEfRO29qdmS3Y3XzJIFxd3C2b4Ppdy=>NVzVWWtNOjR7MkiyNFU>
A549M{e0U2N6fG:6aXPpeJkh[XO|YYm=MorFglIxKM7:TR?=MmO4SG1UVw>?MYfpcoR2[2W|IHH1eI9xcGGpeR?=M1m3UlI1QTJ6MkC1
H1299NWHVUVIyS3m2b4jpZ4l1gSCjc4PhfS=>MlKwglIxKM7:TR?=NHm2e|JFVVORMkPlbY5lfWOnczDheZRweGijZ4m=NH3KWmgzPDl{OEKwOS=>
A549M3;zUmZ2dmO2aX;uJIF{e2G7NXzsfJY{hjJyIN88US=>MnTsSG1UVw>?NWXPXphmcW6lcnXhd4V{KEqQSzDhcoQheDN6IF3BVGsheGixc4Doc5J6dGG2aX;uNYS4WJptOjR7MkiyNFU>
H1299M1z1WGZ2dmO2aX;uJIF{e2G7NEPzV|F,OjBizszNM17JZ2ROW09?NWjQTIZHcW6lcnXhd4V{KEqQSzDhcoQheDN6IF3BVGsheGixc4Doc5J6dGG2aX;uMoDVNlQ6Ojh{MEW=

... Click to View More Cell Line Experimental Data

In vivo In xenograft models, LY2603618 delays tumor growth when given in combination with pemetrexed. [3]
Features

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Dai Y, et al. Clin Cancer Res, 2010, 16(2), 376-383.

[2] Emiliano Calvo1, et al. Mol Cancer Ther, 2011, A94.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-06-25)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01358968 Completed Cancer Eli Lilly and Company June 2011 Phase 1
NCT01341457 Active, not recruiting Solid Tumors Eli Lilly and Company May 2011 Phase 1
NCT01139775 Completed Non Small Cell Lung Cancer Eli Lilly and Company February 2011 Phase 1|Phase 2
NCT01296568 Completed Advanced Cancer Eli Lilly and Company February 2011 Phase 1
NCT00988858 Completed Non Small Cell Lung Cancer Eli Lilly and Company November 2009 Phase 2

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Chemical Information

Download LY2603618 SDF
Molecular Weight (MW) 436.3
Formula

C18H22BrN5O3

CAS No. 911222-45-2
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms IC-83
Solubility (25°C) * In vitro DMSO 13 mg/mL (29.79 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 2% DMSO+30% PEG400+0.5% Tween80+5% Propylene glycol 30mg/mL
* <1 mg/ml means slightly soluble or 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 Name (S)-1-(5-bromo-4-methyl-2-(morpholin-2-ylmethoxy)phenyl)-3-(5-methylpyrazin-2-yl)urea

Customer Product Validation(5)


Click to enlarge
Rating
Source Cancer Lett 2014 10.1016/j.canlet.2014.10.015. LY2603618 purchased from Selleck
Method Western blot
Cell Lines BxPC-3 cells
Concentrations 500 nM
Incubation Time 48 h
Results To determine if CHK1 plays a critical role in MK-1775 sensitivity, it investigated the combination of MK-1775 with LY2603618, a CHK1 selective inhibitor, in BxPC-3 cells. Treatment with 500 nM LY2603618 with MK-1775 resulted in substantially increased PARP cleavage. In contrast to roscovitine, LY2603618 substantially increased γH2AX levels induced by MK-1775 treatment.

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Rating
Source J Hematol Oncol 2014 7, 53. LY2603618 purchased from Selleck
Method Western blot
Cell Lines U937, CTS cells
Concentrations 0.25 uM
Incubation Time 8 h
Results γH2AX levels were increased after MK-1775 treatment, which was further increased by the addition of LY2603618.

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Rating
Source BMC Cancer 2014 14, 483. LY2603618 purchased from Selleck
Method Western blot
Cell Lines HT29 cells
Concentrations 0-1000 nM
Incubation Time 24 h
Results Biomarker responses were subsequently evaluated in HT29 cells treated with gemcitabine or camptothecin in combination with V158411, LY2603618, MK-8776 or GNE-900. In combination with gemcitabine or camptothecin, 100 or 300 nM V158411, LY2603618, MK-8776 and GNE-900 induced a dose dependent decrease in Chk1 phosphorylation at S296 and S317 and a concomitant increase inγ H2AX protein compared to camptothecin alone.

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Rating
Source Customer W, F. Z. LY2603618 purchased from Selleck
Method Western blot
Cell Lines C6 cell
Concentrations 1-20 uM
Incubation Time 24 h
Results CHK1 phosphorylation increased at 1 and 5uM of LY2603618. At even 20uM, CHK1 phosphorylation was not inhibited. These are possibly due to a strong negative feedback, or to prevention of phosphatase proximity. DNA damage indicator, H2AX phosphorylation, was evident at as low as 1uM.

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Rating
Source LY2603618 purchased from Selleck
Method Western blot
Cell Lines HeLa cells
Concentrations 5-25 uM
Incubation Time 24 h
Results CHK1 phosphorylation dramatically increased at 5 and 10uM of LY2603618, possibly due to a strong negative feedback, or to prevention of phosphatase proximity. At 25uM, CHK1 phosphorylation was inhibited.

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.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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