MK-1775 化学構造
分子量: 500.6

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Quality Control & MSDS

製品説明

  • Compare Wee1 Inhibitors
    Wee1製品生物活性の比較
  • 研究分野
  • Combination Therapy
    併用療法

製品の説明

生物活性

製品説明 MK-1775は、有力で選択的なWee1</b> 阻害剤で、IC50 が 5.2 nMです。
ターゲット

Wee1

IC50

5.2 nM [1]

In vitro試験 MK-1775 inhibits Wee1 kinase in an ATP-competitive manner. Compared to Wee1, MK-1775 displays 2- to 3-fold less potency against Yes with IC50 of 14 nM, 10-fold less potency against seven other kinases with >80% inhibition at 1 μM, and >100-fold selectivity over human Myt 1, another kinase that inhibits cyclin-dependent kinase 1 (CDC2) by phosphorylation at an alternative site (Thr14). By abrogating the DNA damage checkpoint via blockade of Wee1 activity in WiDr cells bearing mutated p53, MK-1775 treatment inhibits the basal phosphorylation of CDC2 at Tyr15 (CDC2Y15) with EC50 of 49 nM, and suppresses gemcitabine-, carboplatin- or cisplatin-induced phosphorylation of CDC2 and cell cycle arrest in a dose-dependent manner, with EC50 of 82 nM and 81 nM, 180 nM and 163 nM, as well as 159 nM and 160 nM, respectively. MK-1775 treatment alone at 30-100 nM has no significant antiproliferative effect in WiDr and H1299 cells, whereas MK-1775 at 300 nM, sufficient to inhibit Wee1 by >80%, displays moderate but significant antiproliferative effects by 34.1% in WiDr cells and 28.4% in H1299 cells. [1]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
ASPC-1 MljLS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHLaRY5KSzVyPUGzMlIhyrFiMT6xJO69VQ>? NFPae40zPTR3OEm1OC=>
BxPC-3 MmTsS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWjtVmNnUUN3ME2wMlghyrFiMD6wN{DPxE1? NXXmTWl6OjV2NUi5OVQ>
CFPAC-1 MXLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mn;DTWM2OD1|LkOgxtEhOC5{IN88US=> NYq0cplEOjV2NUi5OVQ>
HPAC NVjFcFg1T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHfGPGhKSzVyPUCuOUDDuSByLkCxJO69VQ>? M1[3N|I2PDV6OUW0
MIAPaCa-2 MYPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MkHzTWM2OD1yLkWgxtEhOC5yNTFOwG0> NH7WdJkzPTR3OEm1OC=>
PANC-1 NXHzT|ZUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWHOXWpmUUN3ME2xNE43KMLzIEGuNUDPxE1? NUG0WnRDOjV2NUi5OVQ>
SK-N-BE (2) NUXocpBJT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGD1dItKSzVyPUKuOQKBkcLz4pEJNE4{KM7:TR?= M2iwcFI2OzB6OUG2
SK-N-BE (2), PAN→MK NHX4fYRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXvJR|UxRTJ4LkdihKnDueLCiUmuOkDPxE1? MViyOVMxQDlzNh?=
SK-N-BE (2), MK→PAN MljXS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlrtTWM2OD1{LkVihKnDueLCiUCuN{DPxE1? MlXxNlU{ODh7MU[=
SK-N-AS M17qZ2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYr3WFVFUUN3ME2wMlUx6oDLwsJihKkxNjB{IN88US=> M1L6NFI2OzB6OUG2
SK-N-DZ Ml\HS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M363PGlEPTB;MD6zOwKBkcLz4pEJNE4xOSEQvF2= MX[yOVMxQDlzNh?=
SK-N-AS Ml\mRZBweHSxc3nzJGF{e2G7 NI\wOYw2ODBibl2= MkfEOFghcA>? M1m4Wolv\HWlZYOgZ4VtdCCjcH;weI9{cXN? NV\kNmpmOjV|MEi5NVY>
SK-N-DZ NELlUI5CeG:ydH;zbZMhSXO|YYm= NIW2fFE2ODBibl2= MlPGOFghcA>? Mk\YbY5lfWOnczDj[YxtKGGyb4D0c5Nqew>? MWKyOVMxQDlzNh?=
THP-1 MWXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2rOblEzPS9{NUCvOVAxKG6P M1[4SFQ5KGh? NWrzdXM{cW6lcnXhd4V{KGOnbHyg[IVifGhiaX6gZUBkd26lZX70doF1cW:wLXTldIVv\GWwdDDtZY5v\XJ? MWKyOVA5PDZzNB?=
MV4-11 M4\kfGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlTzNVI2NzJ3MD:1NFAhdk1? M2HUXVQ5KGh? NWXGPFdLcW6lcnXhd4V{KGOnbHyg[IVifGhiaX6gZUBkd26lZX70doF1cW:wLXTldIVv\GWwdDDtZY5v\XJ? M{jNOFI2ODh2NkG0
U937 NYjjO4p1T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MYqxNlUwOjVyL{WwNEBvVQ>? NFzJNZM1QCCq MY\pcoNz\WG|ZYOgZ4VtdCCmZXH0bEBqdiCjIHPvcoNmdnS{YYTpc44u\GWyZX7k[Y51KG2jbn7ldi=> NXfEc3RHOjVyOES2NVQ>
HL-60 M4Xr[mdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYG0TWZ1OTJ3L{K1NE82ODBibl2= MV60PEBp MYTpcoNz\WG|ZYOgZ4VtdCCmZXH0bEBqdiCjIHPvcoNmdnS{YYTpc44u\GWyZX7k[Y51KG2jbn7ldi=> MkPjNlUxQDR4MUS=
OCI-AML3 MYTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MVqxNlUwOjVyL{WwNEBvVQ>? MYe0PEBp MWDpcoNz\WG|ZYOgZ4VtdCCmZXH0bEBqdiCjIHPvcoNmdnS{YYTpc44u\GWyZX7k[Y51KG2jbn7ldi=> NXzhVoROOjVyOES2NVQ>
MOLM-13 NV\kO21mT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1XaWVEzPS9{NUCvOVAxKG6P NULlN2h1PDhiaB?= NEHhOGFqdmO{ZXHz[ZMh[2WubDDk[YF1cCCrbjDhJINwdmOnboTyZZRqd25vZHXw[Y5l\W62IH3hco5meg>? NXXY[mR[OjVyOES2NVQ>
CMK NXXhUlI6S2WubDDWbYFjcWyrdImgRZN{[Xl? NUfsNJFmOTBvMUCwNFAhdk1? MXy3NkBp MX3y[YR2[2W|IHPlcIwhfmmjbHnibZR6KGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz NEXkSYUzPDl4MkOzNS=>
CMY NUPk[2h4S2WubDDWbYFjcWyrdImgRZN{[Xl? Ml61NVAuOTByMECgcm0> M1voSVczKGh? MUDy[YR2[2W|IHPlcIwhfmmjbHnibZR6KGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz MojpNlQ6PjJ|M{G=
Dayo NGfSNFBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MV3JR|UxRTF3MDDuUS=> NILtT3IzPDZ4MUmxNC=>
UW228 NXP3VoxtT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWXJR|UxRTJ|MjDuUS=> Mn;xNlQ3PjF7MUC=
IST-MES1 MVrD[YxtKF[rYXLpcIl1gSCDc4PhfS=> MlzsNVUxNzJ3MDDuUS=> NGnxPHo4OiCq M1O4SoVvcGGwY3XzJJRp\SClaYPwcIF1cW5iY4n0c5RwgGmlIHXm[oVkfCCrbjDhJINwdmOnboTyZZRqd25vZHXw[Y5l\W62IH3hco5meg>? NGDXZW8zPDN4NUe4Ni=>
IST-MES2 NGPWS3JE\WyuIG\pZYJqdGm2eTDBd5NigQ>? M1XnW|E2OC9{NUCgcm0> NFjZWIQ4OiCq NFLMUXNmdmijbnPld{B1cGViY3nzdIxifGmwIHP5eI91d3irYzDl[oZm[3RiaX6gZUBkd26lZX70doF1cW:wLXTldIVv\GWwdDDtZY5v\XJ? MViyOFM3PTd6Mh?=
REN NWfFR3JRS2WubDDWbYFjcWyrdImgRZN{[Xl? Mn\1NVUxNzJ3MDDuUS=> NXy1eVRnPzJiaB?= MnnR[Y5p[W6lZYOgeIhmKGOrc4DsZZRqdiCleYTveI95cWNiZX\m[YN1KGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz NH[zcGgzPDN4NUe4Ni=>
NCI-H2452 NWXZUVdtS2WubDDWbYFjcWyrdImgRZN{[Xl? NHfWdYQyPTBxMkWwJI5O MkL5O|IhcA>? MYDlcohidmOnczD0bIUh[2m|cHzheIlvKGO7dH;0c5hq[yCnZn\lZ5QhcW5iYTDjc45k\W62cnH0bY9vNWSncHXu[IVvfCCvYX7u[ZI> MnzFNlQ{PjV5OEK=
MSTO-211H M{PKPWNmdGxiVnnhZoltcXS7IFHzd4F6 MlXONVUxNzJ3MDDuUS=> NXTIZ2ZPPzJiaB?= M1S3W4VvcGGwY3XzJJRp\SClaYPwcIF1cW5iY4n0c5RwgGmlIHXm[oVkfCCrbjDhJINwdmOnboTyZZRqd25vZHXw[Y5l\W62IH3hco5meg>? M13VTlI1OzZ3N{iy
NCI-H2052 NH;Ob2pE\WyuIG\pZYJqdGm2eTDBd5NigQ>? MXKxOVAwOjVyIH7N MXq3NkBp M3HvZoVvcGGwY3XzJJRp\SClaYPwcIF1cW5iY4n0c5RwgGmlIHXm[oVkfCCrbjDhJINwdmOnboTyZZRqd25vZHXw[Y5l\W62IH3hco5meg>? MU[yOFM3PTd6Mh?=
WEE1 MVLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3TGUGlEPTB;NT6yJI5O NYHsUXZCOjN4OUm2OVU>
CDC2 M3vxbGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlHxTWM2OO,:nkGwNFAhdk1? NXPzTnBIOjN4OUm2OVU>
CDK7 NImzS4JIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MX3JR|Ux97zgMUCwNEBvVQ>? MkS3NlM3QTl4NUW=
MYT1 M3zDSmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MUXJR|UxRTV|MDDuUS=> MWWyN|Y6QTZ3NR?=
T98G  NGDQ[2tCeG:ydH;zbZMhSXO|YYm= MlzRNVAxNzJ3MDDuUS=> M4XGfVYhcA>? MnPC[Y5p[W6lZYOgdoFlcWG2aX;uMYlv\HWlZXSgZ4VtdCCtaXzsbY5o Mm\VNlE6QTJ5OUO=
A549 NGPl[HpCeG:ydH;zbZMhSXO|YYm= MX:yNFAhdk1? M3nZPVEhcA>? MYDyZYRqd3OnboPpeIl7\XNiTmPDUGMh[2WubIOgbY4h[SCyNUOt[IVx\W6mZX70JI1idm6nch?= M2jYO|IyPzl7MEOz
H460 NWT3ZoNrSXCxcITvd4l{KEG|c3H5 Mo\YNlAxKG6P NFftbmQyKGh? MlrFdoFlcW:|ZX7zbZRqgmW|IF7TR2xEKGOnbHzzJIlvKGFicEWzMYRmeGWwZHXueEBu[W6wZYK= NXfWVXBkOjF5OUmwN|M>
H1299 M{Tic2Fxd3C2b4Ppd{BCe3OjeR?= MWSyNFAhdk1? NUXkNWVQOSCq M4H0epJi\Gmxc3Xud4l1cXqnczDOV2NNSyClZXzsd{BqdiCjIIC1N{1l\XCnbnTlcpQhdWGwbnXy MoXjNlE4QTlyM{O=
Calu-6  NETlbGdCeG:ydH;zbZMhSXO|YYm= NXXifHNQOjByIH7N MU[xJIg> NH62WGFz[WSrb4PlcpNqfGm8ZYOgUnNEVENiY3XscJMhcW5iYTDwOVMu\GWyZX7k[Y51KG2jbn7ldi=> NXTaVJJWOjF5OUmwN|M>
WiDr MlvsT4lv[XOnIFHzd4F6ew>? NGXNdIsyOC1zMECwNEBvVQ>? MWG4JIg> M3HzVolvcGmkaYTzJJBpd3OyaH;yfYxifGmxbjDv[kBETEN{IHH0JHR6ejF3IIfpeIgh[W5iRVO1NOKhfmGudXWgc4YhQDVibn3vcE9NKHC{ZYTy[YF1\WRid3n0bEBo\W2laYThZolv\Q>? Mm\yNVk5QDd3NEW=

... Click to View More Cell Line Experimental Data

In vivo試験 MK-1775 treatment alone at ~20 mg/kg displays minimal antitumor effects against WiDr xenografts in rats with T/C of 69% at day 3. Antitumor efficacy by MK-1775 alone in the nude rat HeLa-luc and TOV21G-shp53 xenograft models is also moderate. [1]
臨床試験 A Phase I dose escalation study evaluating MK-1775 in both monotherapy and in combination with Gemcitabine, Cisplatin, or Carboplatin in adult subjects with advanced solid tumors is currently ongoing.
特集 The first reported Wee1 inhibitor.

プロトコル (参考用のみ)

キナーゼアッセイ:

[1]

In vitro kinase assays Recombinant human Wee1 is used. Kinase reaction is conducted with 10 μM ATP, 1.0 μCi of [γ-33P]ATP, and 2.5 μg of poly(Lys, Tyr) as a substrate in the presence of increasing concentrations of MK-1775 at 30°C for 30 minutes. Radioactivity incorporated into the substrate is trapped on MultiScreen-PH plates and is counted on a liquid scintillation counter.

細胞アッセイ:

[1]

細胞株 WiDr, NCI-H1299, TOV21G, and HeLa
濃度 Dissolved in DMSO, final concentrations ~10 μM
反応時間 24 hours
実験の流れ

Cells are treated with or without gemcitabine for 24 hours, then with MK-1775 for an additional 24 hours. Cell viability is determined with a WST-8 kit using SpectraMax. Cellular caspase-3/7 activities are determined with a Caspase-3/7 Glo kit.

動物実験:

[1]

動物モデル Immunodeficient nude rats (F344/NJcl-rnu) bearing WiDr, HeLa-luc, or TOV21G-shp53 tumors
製剤 Prepared in a vehicle of 0.5% methylcellulose solution
投薬量 ~20 mg/kg/day
投与方法 Orally

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-1775 SDF
分子量 500.6
化学式

C27H32N8O2

CAS No. 955365-80-7
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 80 mg/mL (159.8 mM)
0.0001 mg/mL (0.0 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 2% DMSO+30% PEG 300+5% Tween+ddH2O 5mg/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 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(4-(4-methylpiperazin-1-yl)phenylamino)-1,2-dihydropyrazolo[3,4-d]pyrimidin-3-one

カスタマーフィードバック (5)


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Source , , Cancer Letters, 2015, 356(200): 656–668 . MK-1775 purchased from Selleck
Method H&E Staining
Cell Lines Mice bearing BxPC-3 xenograft tumors
Concentrations 20 mg/kg
Incubation Time 3 weeks
Results Individual drug treatment resulted in increased tumor necrosis, which was further increased following combination treatment, as indicated by H&E staining.

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Source J Hematol Oncol, 2014, 7:53. MK-1775 purchased from Selleck
Method Western blot
Cell Lines AML, HL-60, HL-60/Ara-C cells
Concentrations 125, 250, 500 uM
Incubation Time 48 h
Results There was a concentration-dependent increase in apoptotic cells for the HL60/Ara-C cell line, whereas the parental cell line remained relatively unaffected by MK-1775 concentrations up to 500 nM. A concentration-dependent decrease in p-CDK1 and p-CDK2 accompanied by increase of γH2AX was detected in cells from patient AML#10 as well as in HL60/Ara-C. HL60 cells treated with 500 nM MK-1775 had a small increase of γH2AX and no change in p-CDK1 or p-CDK2, probably due to very low levels of expression prior to drug treatment.

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Source Endocrinology, 2013, 154(9), 3219-27. MK-1775 purchased from Selleck
Method Western blot
Cell Lines T47D cells
Concentrations 1 uM
Incubation Time 2 h
Results To examine how ERK is activated in T47D cells, specific inhibitors of JAK2 (AZD1480) and EGFR (AG1478) were used. It found that pharmacological blockade of either EGFR or JAK2 reduced the phosphorylation of both STAT5 and ERK by GH.

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Source PLoS One, 2013, 8(3), e57523. MK-1775 purchased from Selleck
Method Histopathological assessment
Cell Lines
Concentrations 30 mg/kg
Incubation Time 48 h
Results Additionally, the tumor cells in the MK-1775 alone and MK-1775+ gemcitabine groups exhibited increased cell size with abundant eosinophilic cytoplasm and significant osteoid production, consistent with differentiation. tumors treated with MK-1775 alone and with MK-1775+ gemcitabine had an increased Ki67 index of 73% and 79%. In the vehicle-and gemcitabine-treated tumors, caspase activity was observed in 2% and 6% of tumor cells, respectively. Despite the lack of apoptotic cell death, gemcitabine-treated tumors revealed a significant increase (96%) in γH2AX immunoreactivity compared to the control groups, demonstrating that treatment causes DNA damage but fails to induce cytotoxic response.

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Rating
Source Oncol Rep, 2014, 32(5), 1991-8. MK-1775 purchased from Selleck
Method Immunofluorescence
Cell Lines HT29 cells
Concentrations 1 uM
Incubation Time 2 h
Results HT29 cells were treated with the indicated doses of AZD1480 for 2 h prior to the 2 h stimulation with IL-6. The cells were fixed and stained by the anti-phosphorylated STAT3 primary antibody and the FITC-conjugated secondary antibody. The nucleus was stained with DAPI. Figure shows that phosphorylated STAT3 and non-activated STAT3 are almost located in the cytoplasm instead of the nucleus. Thus, STAT3 translocates to the nucleus when activated.

文献中の引用 (8)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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