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 NHXnd2dIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NYrPZ2dmOjByL{KwNFAhdk1? NWThcFN{OjRiaB?= M2W3eoRm[3KnYYPld{B1cGViSVO1NEBw\iCJZX3jbZRi[mmwZR?= NGL1[o0zPDN3OUWyOi=>
HCT115 MV3Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWjZWGg6OjByL{KwNFAhdk1? MmnpNlQhcA>? Mmix[IVkemWjc3XzJJRp\SCLQ{WwJI9nKEenbXPpeIFjcW6n NVPEb|BTOjR|NUm1NlY>
SW620 MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHrPUmYzODBxMkCwNEBvVQ>? M{C5VlI1KGh? Ml;T[IVkemWjc3XzJJRp\SCLQ{WwJI9nKEenbXPpeIFjcW6n MknhNlQ{PTl3Mk[=
IGROV-1 NYj3RYFHT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NH\lZnczODBxMkCwNEBvVQ>? M1vHVVI1KGh? Mln3[IVkemWjc3XzJJRp\SCLQ{WwJI9nKEenbXPpeIFjcW6n NH;1XWMzPDN3OUWyOi=>
HCT116 NHHsVpZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M4LJfVIxOC9{MECwJI5O NFPZR3QzPCCq NVzSVYRu\GWlcnXhd4V{KHSqZTDJR|UxKG:oIFflcYNqfGGkaX7l M3XKO|I1OzV7NUK2
MCF10A NUfhNHNKT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NYDuZ4lmOjByL{KwNFAhdk1? NUXqTJlsOjRiaB?= MYfk[YNz\WG|ZYOgeIhmKEmFNUCgc4YhT2WvY3n0ZYJqdmV? MWSyOFM2QTV{Nh?=
MiaPaCa-2 MYDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NUS1bFlQOjByL{KwNFAhdk1? NXj6OWNZOjRiaB?= M4HqeIRm[3KnYYPld{B1cGViSVO1NEBw\iCJZX3jbZRi[mmwZR?= MUOyOFM2QTV{Nh?=
MDA-MB-231 NGfCdJhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= Mmj2NlAxNzJyMECgcm0> NFm2[mgzPCCq M3vGVoRm[3KnYYPld{B1cGViSVO1NEBw\iCJZX3jbZRi[mmwZR?= Ml;ZNlQ{PTl3Mk[=
HCC2998 M2Dwfmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NEfBSJozODBxMkCwNEBvVQ>? MkDuNlQhcA>? M1mxSYRm[3KnYYPld{B1cGViSVO1NEBw\iCJZX3jbZRi[mmwZR?= NVHKfmk2OjR|NUm1NlY>
U87 NFXaNG1Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MkTQNlAxNzJyMECgcm0> MYWyOEBp MVXk[YNz\WG|ZYOgeIhmKEmFNUCgc4YhT2WvY3n0ZYJqdmV? M1ezSlI1OzV7NUK2
MDA-MB-435 NGP5NG9Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVnmbIZtOjByL{KwNFAhdk1? M1uyclI1KGh? M3K1eYRm[3KnYYPld{B1cGViSVO1NEBw\iCJZX3jbZRi[mmwZR?= MoW1NlQ{PTl3Mk[=
SNB19 MUfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{f5SFIxOC9{MECwJI5O M2TOUFI1KGh? NX24bGFz\GWlcnXhd4V{KHSqZTDJR|UxKG:oIFflcYNqfGGkaX7l NYHFSHk4OjR|NUm1NlY>
U20S M{TyN2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHHHXHAzODBxMkCwNEBvVQ>? M{\YS|I1KGh? NVLNW21I\GWlcnXhd4V{KHSqZTDJR|UxKG:oIFflcYNqfGGkaX7l Ml7CNlQ{PTl3Mk[=
A498 NHXvT|lIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NYn6XXdmOjByL{KwNFAhdk1? NIXJVo4zPCCq MWnk[YNz\WG|ZYOgeIhmKEmFNUCgc4YhT2WvY3n0ZYJqdmV? M2fGUVI1OzV7NUK2
TK10 M3:xW2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mor3NlAxNzJyMECgcm0> MUeyOEBp MkK3[IVkemWjc3XzJJRp\SCLQ{WwJI9nKEenbXPpeIFjcW6n MYKyOFM2QTV{Nh?=
AsPC-1 NVHTbW5RT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnjoNlAxNzJyMECgcm0> MV[yOEBp NIjZdGxl\WO{ZXHz[ZMhfGinIFnDOVAhd2ZiR3XtZ4l1[WKrbnW= MYqyOFM2QTV{Nh?=
H23 M2rnb2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHL4dXg2ODBibl2= NITwVo4zPCCq NXzHUWpzTE2VTx?= Ml3N[Y5p[W6lZYOgeIhmKGOqZX3vd4Vve2m2aYrheIlwdiC2bzDQUXg> MU[yOFEyOzV2OR?=
H1437 M1SwcWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1zvflUxOCCwTR?= NWruXWR5OjRiaB?= NFu3XYZFVVOR M3fHdYVvcGGwY3XzJJRp\SClaHXtc5NmdnOrdHn6ZZRqd25idH:gVG1Z MlS2NlQyOTN3NEm=
H1993 NVXzW3liT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mm\TOVAxKG6P MYOyOEBp MWHEUXNQ MmXQ[Y5p[W6lZYOgeIhmKGOqZX3vd4Vve2m2aYrheIlwdiC2bzDQUXg> NX;qRpg{OjRzMUO1OFk>
H1299 NHTPUnlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M4Tqb|UxOCCwTR?= M3e2[lI1KGh? NVzVRlYzTE2VTx?= MXXlcohidmOnczD0bIUh[2inbX;z[Y5{cXSrenH0bY9vKHSxIGDNXC=> MY[yOFEyOzV2OR?=
AsPC-1 M{\ZcGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYiwcnNbOTBvMUCwNEBvVQ>? MWCyOE01QGh? NHPLXGxmdmijbnPld{B1cGViY3jlcY9{\W6|aYTpfoF1cW:wIITvJIdmdWOrdHHibY5m M3\IdlI{QDB2NEKy
MiaPaCa-2 MoXvS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NEX5NlQyOC1zMECwJI5O NITYWpgzPC12OHi= NWTYOWJY\W6qYX7j[ZMhfGinIHPo[Y1we2Wwc3n0bZpifGmxbjD0c{Bo\W2laYThZolv\Q>? MnToNlM5ODR2MkK=
BxPC-3 M3HqRWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3PycFExNTFyMECgcm0> MnjvNlQuPDiq NFXre|NmdmijbnPld{B1cGViY3jlcY9{\W6|aYTpfoF1cW:wIITvJIdmdWOrdHHibY5m NELOR|czOzhyNESyNi=>
SKOV3 MU\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVzYU3c{OC5|INM1US=> NFnrTVY5KGR? MmHHd4Vve2m2aYrld{B1cGViY3XscEBtcW6nczD0c{Bo\W2laYThZolv\cLi MkHDNlM2PDh{Nkm=
OVCAR-8 NV;L[nY2T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MXOwMlMhyrWP NXm1cWtSQCCm M1;JcpNmdnOrdHn6[ZMhfGinIHPlcIwhdGmwZYOgeI8h\2WvY3n0ZYJqdmYEoB?= M1rR[|I{PTR6Mk[5
MV-4-11 MoLGRZBweHSxc3nzJGF{e2G7 MYCxNFAuPzByIH7N Ml\6OFghcA>? NWm1[WpjcW6mdXPld{BieG:ydH;zbZMh\G:|ZTDk[ZBmdmSnboTsfS=> MmjPNlM2OzZ5MkG=
U937 M1jlcWFxd3C2b4Ppd{BCe3OjeR?= NFHFV|YyODBvN{CwJI5O Moi2OFghcA>? NIT0UWVqdmS3Y3XzJIFxd3C2b4Ppd{Bld3OnIHTldIVv\GWwdHz5 NXLmVYo3OjN3M{[3NlE>
MOLM-13  MoPrRZBweHSxc3nzJGF{e2G7 NGWzWnUyODBvN{CwJI5O NFLMWFU1QCCq Ml\2bY5lfWOnczDhdI9xfG:|aYOg[I9{\SCmZYDlcoRmdnSueR?= Mn2yNlM2OzZ5MkG=
A2058  MmfBR4VtdCCYaXHibYxqfHliQYPzZZk> NHjEVoU{Py53LUOwNEBvVQ>? MYe3NkBp NULtUW96TE2VTx?= NI\WdG1z\WS3Y3XzJJRp\SCPSz2xO|c2KEWFNUFCpIJ6KDVvZn;s[EB1dyCjbjDheoVz[WenIH;mJFQ2KG6P NVr4S3I2OjNzNEi2PFQ>
H2009 NV63OJdoS2WubDDWbYFjcWyrdImgRZN{[Xl? MWm1NFAhdk1? NH:1NWo4OiCq MkfYSG1UVw>? MlrxdoV{fWy2czDpckBIOS:VLYDoZZNmKGGlY4XteYxifGmxbjDjc41jcW6nZDD3bZRpKE2NLUG3O|U> M1nYW|I{OTR6Nki0
Su.86.86 M4rCU2NmdGxiVnnhZoltcXS7IFHzd4F6 Mnu4OVAxKG6P NXjpSpp1PzJiaB?= NF32OJVFVVOR MnqwdoV{fWy2czDpckBIOS:VLYDoZZNmKGGlY4XteYxifGmxbjDjc41jcW6nZDD3bZRpKE2NLUG3O|U> MoLzNlMyPDh4OES=
HRE NXPPbpV3S2WubDDWbYFjcWyrdImgRZN{[Xl? NWDEXXJXPTByIH7N NYHyWXdxPzJiaB?= NYTMVpdMTE2VTx?= M4\i[JJme3WudIOgbY4hTzFxUz3wbIF{\SCjY3P1cZVt[XSrb36gZ49u[mmwZXSge4l1cCCPSz2xO|c2 M{PHPFI{OTR6Nki0
HMEC M2fiNGNmdGxiVnnhZoltcXS7IFHzd4F6 MWi1NFAhdk1? NF30[2s4OiCq MmrGSG1UVw>? M1;ENJJme3WudIOgbY4hTzFxUz3wbIF{\SCjY3P1cZVt[XSrb36gZ49u[mmwZXSge4l1cCCPSz2xO|c2 MoDaNlMyPDh4OES=
U2OS  NGfJ[YRHfW6ldHnvckBCe3OjeR?= NWD4O|k3OiEEtV2= NYXOS2tIOC1{NDDo M3[xNIlv\HWlZYOgdIhwe3Cqb4L5cIF1cW:wIH;mJGNpczFiYYSgd4VzcW6nIEO0OUBifCCkb4ToJINwdmOnboTyZZRqd26|IHHzJIViemy7IHHzJFIhcCCjZoTldkBi\G2rbnnzeJJifGmxbh?= NFPkdZgzOjl|N{G0Oy=>
U2OS  NWnQd28{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1Hqb|AuOTBiwsXN NFPjPXAzPC92ODDo NVrmZlUycW6qaXLpeJMh[2WubDDndo94fGhiZH;z[UBl\XCnbnTlcpRtgQ>? MWiyNlk{PzF2Nx?=
U937 M3O0cGZ2dmO2aX;uJGF{e2G7 MXKxNFAuPTByIH7N MV[0JIjDqA>? Mo\V[IVkemWjc3XzJJRp\SCleYThdoFjcW6nLXnu[JVk\WRiQ3jrNUBifXSxcHjvd5Bpd3K7bHH0bY9vKGG2IGPldlI6PsLiYX7kJJBz\X[nboTzJGNl[zJ3QTDkc5dvemWpdXzheIlwdg>? MV:yNlg3QTh4OR?=
U937 NYHnXJlnTnWwY4Tpc44hSXO|YYm= Ml3uNVAxKG6P NX\YTIlkPCCqwrC= NWPucHpUemW4ZYLz[ZMhfGinIHP5eIFz[WKrbnWtbY5lfWOnZDDpcohq[mm2aX;uJI9nyqB|SD30bJlucWSrbnWgbY5kd3Kyb4LheIlwdiCrboTvJGRPSQ>? MnjuNlI5Pjl6Nkm=
U937 MmjKSpVv[3Srb36gRZN{[Xl? NYLVdZpPOTByLUWwNEBvVQ>? NWDCVXR7PCCqwrC= MUjpcoR2[2W|IHnuZ5Jm[XOnZDDwbI9{eGixconsZZRqd25ib3[gTFJCYA>? MmPTNlI5Pjl6Nkm=
HL-60 NYnBTHE5SXCxcITvd4l{KEG|c3H5 MmX5N|AwOTByL{OwNEBvVQ>? MVyyOEBp NG[2WI9FVVOR Mn;D[Y5p[W6lZYOgZ5l1[XKjYnnu[U1qdmS3Y3XkJIFxd3C2b4Ppdy=> NXTHT2M3OjJ6Nkm4Olk>
ML-1 Mof1RZBweHSxc3nzJGF{e2G7 NUTtT456OjVxNUCvNVAxKG6P NVvVT|NSOjRiaB?= MnG4SG1UVw>? MkW0[Y5p[W6lZYOgZ5l1[XKjYnnu[U1qdmS3Y3XkJIFxd3C2b4Ppdy=> NU\obW1ROjJ6Nkm4Olk>
HCT116 NEPCUJVHfW6ldHnvckBCe3OjeR?= NUf1SoFtOSEEtV2= MnnqNlQhcA>? M{\DVIFjem:pYYTld{Bw\iClZXzsJIN6[2ynIHHydoV{fMLi NFrxcWQzOjVzMEW2NC=>
U2OS Mlv6SpVv[3Srb36gRZN{[Xl? Mm\vNUDDvU1? MXSyOEBp NF74WJJi[nKxZ3H0[ZMhd2ZiY3XscEBkgWOuZTDhdpJme3UEoB?= NVfZdWdNOjJ3MUC1OlA>

... 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