MK-8776 (SCH 900776) 化学構造
分子量: 376.25

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製品説明

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製品の説明

生物活性

製品説明 MK-8776 (SCH 900776)は、選択的なChk1</b> 阻害剤で、IC50 が 3 nMです。
ターゲット Chk1
IC50 3 nM [1]
In vitro試験 SCH 900776 is a less potent inhibitor of Chk2 and CDK2 with IC50 of 1.5 μM and 0.16 μM, respectively. SCH 900776 shows no significant inhibition of cytochrome P450 human liver microsomal isoforms 1A2, 2C9, 2C19, 2D6, and 3A4. SCH 900776 induces a dose-dependent loss of DNA replication capability 24 hours after hydroxyurea exposure. SCH 900776 enhances the γ-H2AX response of hydroxyurea, 5-fluoruracil, and cytarabine. In combination with an antimetabolite, SCH 900776 induces accumulation of γ-H2AX within 2 hours, indicative of replication fork collapse and double stranded DNA breaks. Additionally, SCH 900776 suppresses accumulation of the Chk1 pS296 autophosphorylation in a dose-dependent manner. Exposure of proliferating WS1 cells to SCH 900776 is associated with rapid, dose-dependent accumulation of Chk1 pS345, indicating that cycling populations of normal cells induce Chk1 pS345 following exposure to SCH 900776 as part of a futile cycle, perhaps driven by AT-family kinases and DNA-PK.[1]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
U251 NUPzVJZJT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MV2yNFAwOjByMDDuUS=> NVrmUZplOjRiaB?= MlTM[IVkemWjc3XzJJRp\SCLQ{WwJI9nKEenbXPpeIFjcW6n NGXGbnAzPDN3OUWyOi=>
HCT115 MkXmS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1jDbFIxOC9{MECwJI5O NXyyPYFYOjRiaB?= NUPWb5Bp\GWlcnXhd4V{KHSqZTDJR|UxKG:oIFflcYNqfGGkaX7l MlTpNlQ{PTl3Mk[=
SW620 MmX0S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1m2dlIxOC9{MECwJI5O M{foSFI1KGh? NVjTbVls\GWlcnXhd4V{KHSqZTDJR|UxKG:oIFflcYNqfGGkaX7l NV3EU45pOjR|NUm1NlY>
IGROV-1 MnjCS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MojyNlAxNzJyMECgcm0> NILKUGIzPCCq NWHXNVhI\GWlcnXhd4V{KHSqZTDJR|UxKG:oIFflcYNqfGGkaX7l MXOyOFM2QTV{Nh?=
HCT116 M1HJXWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUTKeWxvOjByL{KwNFAhdk1? M13MRlI1KGh? MXPk[YNz\WG|ZYOgeIhmKEmFNUCgc4YhT2WvY3n0ZYJqdmV? M32wOFI1OzV7NUK2
MCF10A Mn\4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFf3PJEzODBxMkCwNEBvVQ>? NWHISIR5OjRiaB?= MmLN[IVkemWjc3XzJJRp\SCLQ{WwJI9nKEenbXPpeIFjcW6n M3\RelI1OzV7NUK2
MiaPaCa-2 MVfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NW\jSnN5OjByL{KwNFAhdk1? Mo\4NlQhcA>? NUfwe4Fl\GWlcnXhd4V{KHSqZTDJR|UxKG:oIFflcYNqfGGkaX7l MWqyOFM2QTV{Nh?=
MDA-MB-231 MXPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MUWyNFAwOjByMDDuUS=> NHrXS2wzPCCq NX;BUHB2\GWlcnXhd4V{KHSqZTDJR|UxKG:oIFflcYNqfGGkaX7l NH3LNFczPDN3OUWyOi=>
HCC2998 M{LFVmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnvHNlAxNzJyMECgcm0> MXeyOEBp NVTYSGtP\GWlcnXhd4V{KHSqZTDJR|UxKG:oIFflcYNqfGGkaX7l NH[zNVAzPDN3OUWyOi=>
U87 MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M4\5SlIxOC9{MECwJI5O NFrBV3QzPCCq Mn31[IVkemWjc3XzJJRp\SCLQ{WwJI9nKEenbXPpeIFjcW6n MYWyOFM2QTV{Nh?=
MDA-MB-435 MUDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NX7ufWo2OjByL{KwNFAhdk1? NYPtVXhLOjRiaB?= NVPIcWps\GWlcnXhd4V{KHSqZTDJR|UxKG:oIFflcYNqfGGkaX7l NHHlWIUzPDN3OUWyOi=>
SNB19 NF3VcFlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXyyNFAwOjByMDDuUS=> M4n1XVI1KGh? NVnBOZVq\GWlcnXhd4V{KHSqZTDJR|UxKG:oIFflcYNqfGGkaX7l MVmyOFM2QTV{Nh?=
U20S M4jaRWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3;OR|IxOC9{MECwJI5O MoHMNlQhcA>? M3vV[oRm[3KnYYPld{B1cGViSVO1NEBw\iCJZX3jbZRi[mmwZR?= MoLzNlQ{PTl3Mk[=
A498 M4GwVmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M{HUXVIxOC9{MECwJI5O NWG0PI82OjRiaB?= NV;5W5ZO\GWlcnXhd4V{KHSqZTDJR|UxKG:oIFflcYNqfGGkaX7l M2jSW|I1OzV7NUK2
TK10 NIrzdFlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M4jMblIxOC9{MECwJI5O NIDBVWQzPCCq M37NR4Rm[3KnYYPld{B1cGViSVO1NEBw\iCJZX3jbZRi[mmwZR?= MonrNlQ{PTl3Mk[=
AsPC-1 MXTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWn5PWtJOjByL{KwNFAhdk1? MWOyOEBp NGjjd4tl\WO{ZXHz[ZMhfGinIFnDOVAhd2ZiR3XtZ4l1[WKrbnW= M4\hflI1OzV7NUK2
H23 M1P4Vmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NX\hb5R3PTByIH7N MVqyOEBp M{Dz[mROW09? MVPlcohidmOnczD0bIUh[2inbX;z[Y5{cXSrenH0bY9vKHSxIGDNXC=> NUToc5F1OjRzMUO1OFk>
H1437 NF;yS45Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2\jeFUxOCCwTR?= MUGyOEBp NVezcpJUTE2VTx?= M4LP[IVvcGGwY3XzJJRp\SClaHXtc5NmdnOrdHn6ZZRqd25idH:gVG1Z MnL2NlQyOTN3NEm=
H1993 M4rXcWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NWnnWIFlPTByIH7N NYrHSXZQOjRiaB?= M3:0SGROW09? NXS5bZZV\W6qYX7j[ZMhfGinIHPo[Y1we2Wwc3n0bZpifGmxbjD0c{BRVVh? NU\lPYE3OjRzMUO1OFk>
H1299 MnfQS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MY[1NFAhdk1? NHXubGwzPCCq MYHEUXNQ Mn;4[Y5p[W6lZYOgeIhmKGOqZX3vd4Vve2m2aYrheIlwdiC2bzDQUXg> NEX4OZMzPDFzM{W0PS=>
AsPC-1 MUTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWnybVJEOTBvMUCwNEBvVQ>? MWWyOE01QGh? MWDlcohidmOnczD0bIUh[2inbX;z[Y5{cXSrenH0bY9vKHSxIHflcYNqfGGkaX7l M4L2TlI{QDB2NEKy
MiaPaCa-2 NWKxcVZtT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVWxNE0yODByIH7N M1;2XVI1NTR6aB?= NYPnW5lJ\W6qYX7j[ZMhfGinIHPo[Y1we2Wwc3n0bZpifGmxbjD0c{Bo\W2laYThZolv\Q>? NILFbWwzOzhyNESyNi=>
BxPC-3 MXLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NEHBfHQyOC1zMECwJI5O MoSzNlQuPDiq MWjlcohidmOnczD0bIUh[2inbX;z[Y5{cXSrenH0bY9vKHSxIHflcYNqfGGkaX7l NHTPOXozOzhyNESyNi=>
SKOV3 NX7lfYhFT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NIfYS4UxNjNiwsXN MVS4JIQ> Ml3xd4Vve2m2aYrld{B1cGViY3XscEBtcW6nczD0c{Bo\W2laYThZolv\cLi NWXofVk{OjN3NEiyOlk>
OVCAR-8 MlO3S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1jjVFAvOyEEtV2= NFzIO|Q5KGR? M4fXepNmdnOrdHn6[ZMhfGinIHPlcIwhdGmwZYOgeI8h\2WvY3n0ZYJqdmYEoB?= NYHudZZVOjN3NEiyOlk>
MV-4-11 M4HZXWFxd3C2b4Ppd{BCe3OjeR?= M3LBVlExOC15MECgcm0> NInNS|A1QCCq NH\LdIdqdmS3Y3XzJIFxd3C2b4Ppd{Bld3OnIHTldIVv\GWwdHz5 MVqyN|U{Pjd{MR?=
U937 MoHBRZBweHSxc3nzJGF{e2G7 NYTOXJBvOTByLUewNEBvVQ>? MXe0PEBp NVjSNFFCcW6mdXPld{BieG:ydH;zbZMh\G:|ZTDk[ZBmdmSnboTsfS=> NWTNelNDOjN3M{[3NlE>
MOLM-13  M{S4e2Fxd3C2b4Ppd{BCe3OjeR?= M3SwRVExOC15MECgcm0> MUO0PEBp NVSwfmhQcW6mdXPld{BieG:ydH;zbZMh\G:|ZTDk[ZBmdmSnboTsfS=> NV36SoF1OjN3M{[3NlE>
A2058  Ml22R4VtdCCYaXHibYxqfHliQYPzZZk> MmLqN|cvPS1|MECgcm0> M3TGVlczKGh? MUDEUXNQ NH25[opz\WS3Y3XzJJRp\SCPSz2xO|c2KEWFNUFCpIJ6KDVvZn;s[EB1dyCjbjDheoVz[WenIH;mJFQ2KG6P NYrzfm06OjNzNEi2PFQ>
H2009 MXLD[YxtKF[rYXLpcIl1gSCDc4PhfS=> NVvtWGJPPTByIH7N NU\3XZl[PzJiaB?= NWL6WWRtTE2VTx?= MkjNdoV{fWy2czDpckBIOS:VLYDoZZNmKGGlY4XteYxifGmxbjDjc41jcW6nZDD3bZRpKE2NLUG3O|U> NFPlNZczOzF2OE[4OC=>
Su.86.86 NVT5UJVKS2WubDDWbYFjcWyrdImgRZN{[Xl? MUm1NFAhdk1? MkfWO|IhcA>? M{PzTGROW09? MVTy[ZN2dHS|IHnuJGcyN1NvcHjhd4Uh[WOldX31cIF1cW:wIHPvcYJqdmWmIIfpeIghVUtvMUe3OS=> NX;uU|JnOjNzNEi2PFQ>
HRE NF7xcY9E\WyuIG\pZYJqdGm2eTDBd5NigQ>? NYjOTHR4PTByIH7N NXSxPFlSPzJiaB?= M{PyNWROW09? M1zJRZJme3WudIOgbY4hTzFxUz3wbIF{\SCjY3P1cZVt[XSrb36gZ49u[mmwZXSge4l1cCCPSz2xO|c2 NYC4OIJmOjNzNEi2PFQ>
HMEC NGCzVFhE\WyuIG\pZYJqdGm2eTDBd5NigQ>? NWm3bIh{PTByIH7N NEPuUWI4OiCq M2LhUmROW09? MlLDdoV{fWy2czDpckBIOS:VLYDoZZNmKGGlY4XteYxifGmxbjDjc41jcW6nZDD3bZRpKE2NLUG3O|U> NXe1c5VKOjNzNEi2PFQ>
U2OS  NIfCPXpHfW6ldHnvckBCe3OjeR?= M3;hZ|IhyrWP MkTBNE0zPCCq MYLpcoR2[2W|IIDoc5NxcG:{eXzheIlwdiCxZjDDbIsyKGG2IIPldolv\SB|NEWgZZQh[m:2aDDjc45k\W62cnH0bY9veyCjczDlZZJtgSCjczCyJIgh[W[2ZYKgZYRucW6rc4TyZZRqd25? NEj2SVkzOjl|N{G0Oy=>
U2OS  NIfFWlNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3q5TlAuOTBiwsXN NEDNWmczPC92ODDo M{jrS4lvcGmkaYTzJINmdGxiZ4Lve5RpKGSxc3Wg[IVx\W6mZX70cJk> M4HB[FIzQTN5MUS3
U937 NVPBdG9xTnWwY4Tpc44hSXO|YYm= NIHacIsyODBvNUCwJI5O NGi4e3M1KGkEoB?= NIHwXWhl\WO{ZXHz[ZMhfGinIHP5eIFz[WKrbnWtbY5lfWOnZDDDbIsyKGG3dH;wbI9{eGixconsZZRqd25iYYSgV4VzOjl4wrDhcoQheHKndnXueJMhS2SlMkXBJIRwf26{ZXf1cIF1cW:w NVH2PZZIOjJ6Nkm4Olk>
U937 M4HZUGZ2dmO2aX;uJGF{e2G7 Ml7HNVAxKG6P MYm0JIjDqA>? NULIRnh[emW4ZYLz[ZMhfGinIHP5eIFz[WKrbnWtbY5lfWOnZDDpcohq[mm2aX;uJI9nyqB|SD30bJlucWSrbnWgbY5kd3Kyb4LheIlwdiCrboTvJGRPSQ>? MljPNlI5Pjl6Nkm=
U937 MVjGeY5kfGmxbjDBd5NigQ>? MXWxNFAuPTByIH7N NWH2d|NZPCCqwrC= M4DPV4lv\HWlZYOgbY5kemWjc3XkJJBpd3OyaH;yfYxifGmxbjDv[kBJOkG[ Mkf4NlI5Pjl6Nkm=
HL-60 NWjOVpROSXCxcITvd4l{KEG|c3H5 MVuzNE8yODBxM{CwJI5O MUmyOEBp NHLQOohFVVOR MXzlcohidmOnczDjfZRiemGkaX7lMYlv\HWlZXSgZZBweHSxc3nz NVvFSHJ{OjJ6Nkm4Olk>
ML-1 MWHBdI9xfG:|aYOgRZN{[Xl? MUSyOU82OC9zMECgcm0> M3HaSlI1KGh? MoTDSG1UVw>? MYHlcohidmOnczDjfZRiemGkaX7lMYlv\HWlZXSgZZBweHSxc3nz M2HseFIzQDZ7OE[5
HCT116 MXjGeY5kfGmxbjDBd5NigQ>? M2rMelEhyrWP NGTFWngzPCCq MUXhZpJw\2G2ZYOgc4Yh[2WubDDjfYNt\SCjcoLld5TDqA>? M{TkZlIzPTFyNU[w
U2OS NW\PTnlzTnWwY4Tpc44hSXO|YYm= M2jyfVEhyrWP M1r5b|I1KGh? MkTWZYJzd2ejdHXzJI9nKGOnbHygZ5lkdGViYYLy[ZN1yqB? NHrOeFYzOjVzMEW2NC=>

... Click to View More Cell Line Experimental Data

In vivo試験 Administered 30 minutes after gemcitabine, 4 mg/kg SCH 900776 is sufficient to induce the γ-H2AX biomarker while 8 mg/kg leads to enhanced tumor pharmacodynamic and regression responses relative to gemcitabine or SCH 900776 alone. Dose escalation of SCH 900776 (16 mg/kg and 32 mg/kg) induces incremental improvements in tumor response. Importantly, doses of SCH 900776 associate with robust biomarker activation and improved tumor response are not associated with enhanced toxicity of gemcitabine on hematological parameters in BALB/c mice. [1]
臨床試験 A Phase I study of SCH 900776 with and without Gemcitabine in patients with solid tumors or lymphoma has been completed.
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Chk1 SPA assay An in vitro assay utilizing recombinant His-Chk1 expressed in the baculovirus expression system as an enzyme source and biotinylated peptide based upon CDC25C as substrate. His-Chk1 is diluted to 32 nM in kinase buffer containing 50 mM Tris pH 8.0, 10 mM MgCl2, and 1 mM DTT. CDC25C (CDC25 Ser216 C-term biotinylated peptide) peptide is diluted to 1.93 μM in kinase buffer. For each kinase reaction, 20 μL of 32 nM Chk1 enzyme solution and 20 μL of 1.926 μM CDC25C are mixed and combined with 10 μL of SCH 900776 diluted in 10% DMSO, making final reaction concentrations of 6.2 nM Chk1, 385 nM CDC25C and 1% DMSO after addition of start solution. The reaction is started by addition of 50 μL of start solution consisting of 2 μM ATP and 0.2 μCi of 33P-ATP, making a final reaction concentration of 1 μM ATP, with 0.2 μCi of 33P-ATP per reaction. Kinase reactions run for 2 hours at room temperature and are stopped by the addition of 100 μL of stop solution consisting of 2 M NaCl, 1% H3PO4, and 5 mg/mL Streptavidin-coated SPA beads. SPA beads are captured using a 96-well GF/B filter plate and a Filtermate universal harvester. Beads are washed twice with 2 M NaCl and twice with 2 M NaCl with 1% phosphoric acid. Signal is then assayed using a TopCount 96-well liquid scintillation counter. Dose-response curves are generated from duplicate 8 point serial dilutions of SCH 900776. IC50 values are derived by nonlinear regression analysis.

動物実験: [1]

動物モデル Female nude mice injected subcutaneously with A2780 or MiaPaCa2 cells
製剤 Formulated in 20% hydroxypropyl β-cyclodextrin
投薬量 ~50 mg/kg
投与方法 Administered intraperitoneally

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

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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

参考

化学情報

Download MK-8776 (SCH 900776) SDF
分子量 376.25
化学式

C15H18BrN7

CAS No. 891494-63-6
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 3 mg/mL (7.97 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 4% DMSO+30% propylene glycol 5 mg/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.
化学名 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-((R)-piperidin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine

カスタマーフィードバック (1)


Click to enlarge
Rating
Source MK-8776 (SCH 900776) purchased from Selleck
Method Western blot
Cell Lines HeLa cells
Concentrations 1-10 uM
Incubation Time 24 h
Results CHK1 phosphorylation increased at 1uM of MK-8776 (SCH900776), possibly due to a negative feedback, or to prevention of phosphatase proximity. At 10uM, CHK1 phosphorylation was inhibited.

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* 必須

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID