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 NX;NXYJJT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUPPV4tMUUN3ME2xN{4zKMLzIEGuNUDPxE1? NU\oV25tOjV2NUi5OVQ>
BxPC-3 MXjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlT0TWM2OD1yLkigxtEhOC5yMzFOwG0> MVGyOVQ2QDl3NB?=
CFPAC-1 MmfpS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MYjJR|UxRTNwMzFCtUAxNjJizszN NIPRSmEzPTR3OEm1OC=>
HPAC NVziPI1FT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHf4eoFKSzVyPUCuOUDDuSByLkCxJO69VQ>? MlHTNlU1PTh7NUS=
MIAPaCa-2 MWnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXrJR|UxRTBwNTFCtUAxNjB3IN88US=> NYqwT3pwOjV2NUi5OVQ>
PANC-1 M{T6ZWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NX\jdpJrUUN3ME2xNE43KMLzIEGuNUDPxE1? NVjWdItZOjV2NUi5OVQ>
SK-N-BE (2) MVvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYjJR|UxRTJwNPMAjeKy6oDLMD6zJO69VQ>? MljBNlU{ODh7MU[=
SK-N-BE (2), PAN→MK MX\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHnTemhKSzVyPUK2MlbjiIoEsfMAjVkvPiEQvF2= NFX3ZlkzPTNyOEmxOi=>
SK-N-BE (2), MK→PAN NEDT[4hIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NXTuS5ZCUUN3ME2yMlTjiIoEsfMAjVAvOyEQvF2= MWmyOVMxQDlzNh?=
SK-N-AS MWTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MoT2TWM2OD1yLkWw5qCKyrIkgJmwMlAzKM7:TR?= MneyNlU{ODh7MU[=
SK-N-DZ M{iwb2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3vjfGlEPTB;MD6zOwKBkcLz4pEJNE4xOSEQvF2= M2LUW|I2OzB6OUG2
SK-N-AS NYnE[JBLSXCxcITvd4l{KEG|c3H5 MmjQOVAxKG6P MVG0PEBp M1;2T4lv\HWlZYOgZ4VtdCCjcH;weI9{cXN? NGDNUFUzPTNyOEmxOi=>
SK-N-DZ NVHN[pYxSXCxcITvd4l{KEG|c3H5 M4q4[|UxOCCwTR?= NVLQXWdNPDhiaB?= M2ezNolv\HWlZYOgZ4VtdCCjcH;weI9{cXN? MlK1NlU{ODh7MU[=
THP-1 NWTJbVJ6T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NW\GcoczOTJ3L{K1NE82ODBibl2= MWK0PEBp NX[0NYxYcW6lcnXhd4V{KGOnbHyg[IVifGhiaX6gZUBkd26lZX70doF1cW:wLXTldIVv\GWwdDDtZY5v\XJ? NWmzc|Z1OjVyOES2NVQ>
MV4-11 M4HaU2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M{O3b|EzPS9{NUCvOVAxKG6P MmDmOFghcA>? MkfkbY5kemWjc3XzJINmdGxiZHXheIghcW5iYTDjc45k\W62cnH0bY9vNWSncHXu[IVvfCCvYX7u[ZI> M{fMOVI2ODh2NkG0
U937 M2HOVGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYi0SHlHOTJ3L{K1NE82ODBibl2= MmLrOFghcA>? NGX3b5hqdmO{ZXHz[ZMh[2WubDDk[YF1cCCrbjDhJINwdmOnboTyZZRqd25vZHXw[Y5l\W62IH3hco5meg>? NU\PXW5xOjVyOES2NVQ>
HL-60 NUjhe|VjT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NH\rd3kyOjVxMkWwM|UxOCCwTR?= NGDZNIM1QCCq NGnRe2FqdmO{ZXHz[ZMh[2WubDDk[YF1cCCrbjDhJINwdmOnboTyZZRqd25vZHXw[Y5l\W62IH3hco5meg>? MWOyOVA5PDZzNB?=
OCI-AML3 NXzTdFVbT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MmTpNVI2NzJ3MD:1NFAhdk1? NWr4V4E6PDhiaB?= Mo\KbY5kemWjc3XzJINmdGxiZHXheIghcW5iYTDjc45k\W62cnH0bY9vNWSncHXu[IVvfCCvYX7u[ZI> MmTnNlUxQDR4MUS=
MOLM-13 MmXnS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1TYbFEzPS9{NUCvOVAxKG6P MXe0PEBp MVrpcoNz\WG|ZYOgZ4VtdCCmZXH0bEBqdiCjIHPvcoNmdnS{YYTpc44u\GWyZX7k[Y51KG2jbn7ldi=> NFfQT28zPTB6NE[xOC=>
CMK MlnhR4VtdCCYaXHibYxqfHliQYPzZZk> M4fSOlExNTFyMECwJI5O M1nsZlczKGh? MX;y[YR2[2W|IHPlcIwhfmmjbHnibZR6KGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz Ml7YNlQ6PjJ|M{G=
CMY NXWzcZJKS2WubDDWbYFjcWyrdImgRZN{[Xl? Mn3mNVAuOTByMECgcm0> MVy3NkBp MmKxdoVlfWOnczDj[YxtKH[rYXzpZol1gSCrbjDhJINwdmOnboTyZZRqd25vZHXw[Y5l\W62IH3hco5meg>? M1\BSVI1QTZ{M{Ox
Dayo MWTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MWnJR|UxRTF3MDDuUS=> NYjwTmI6OjR4NkG5NVA>
UW228 MofMS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHzITlZKSzVyPUKzNkBvVQ>? NH71PIwzPDZ4MUmxNC=>
IST-MES1 M1vYWmNmdGxiVnnhZoltcXS7IFHzd4F6 MUixOVAwOjVyIH7N M{TFOFczKGh? NGPZdmJmdmijbnPld{B1cGViY3nzdIxifGmwIHP5eI91d3irYzDl[oZm[3RiaX6gZUBkd26lZX70doF1cW:wLXTldIVv\GWwdDDtZY5v\XJ? MWKyOFM3PTd6Mh?=
IST-MES2 Mn;KR4VtdCCYaXHibYxqfHliQYPzZZk> NEH5fWsyPTBxMkWwJI5O M33OZ|czKGh? MVXlcohidmOnczD0bIUh[2m|cHzheIlvKGO7dH;0c5hq[yCnZn\lZ5QhcW5iYTDjc45k\W62cnH0bY9vNWSncHXu[IVvfCCvYX7u[ZI> NGXkbG4zPDN4NUe4Ni=>
REN Mm\5R4VtdCCYaXHibYxqfHliQYPzZZk> M2S3V|E2OC9{NUCgcm0> NGnmeVI4OiCq Mlux[Y5p[W6lZYOgeIhmKGOrc4DsZZRqdiCleYTveI95cWNiZX\m[YN1KGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz NF3uXIUzPDN4NUe4Ni=>
NCI-H2452 NIPsXHVE\WyuIG\pZYJqdGm2eTDBd5NigQ>? MYmxOVAwOjVyIH7N NUnXbVdGPzJiaB?= NGfOS|VmdmijbnPld{B1cGViY3nzdIxifGmwIHP5eI91d3irYzDl[oZm[3RiaX6gZUBkd26lZX70doF1cW:wLXTldIVv\GWwdDDtZY5v\XJ? NEDZXoYzPDN4NUe4Ni=>
MSTO-211H M37X[GNmdGxiVnnhZoltcXS7IFHzd4F6 MVKxOVAwOjVyIH7N MmDvO|IhcA>? MoDZ[Y5p[W6lZYOgeIhmKGOrc4DsZZRqdiCleYTveI95cWNiZX\m[YN1KGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz MWWyOFM3PTd6Mh?=
NCI-H2052 NE\Qd5VE\WyuIG\pZYJqdGm2eTDBd5NigQ>? MkH2NVUxNzJ3MDDuUS=> NHP3cY44OiCq Mk\w[Y5p[W6lZYOgeIhmKGOrc4DsZZRqdiCleYTveI95cWNiZX\m[YN1KGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz Mm\0NlQ{PjV5OEK=
WEE1 NXz2bZd5T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NYSzOm1SUUN3ME21MlIhdk1? MlLkNlM3QTl4NUW=
CDC2 MmWzS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Mm\mTWM2OO,:nkGwNFAhdk1? MU[yN|Y6QTZ3NR?=
CDK7 NXTueHJ7T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHLuU5ZKSzVy78{eNVAxOCCwTR?= MVuyN|Y6QTZ3NR?=
MYT1 MY\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MmLRTWM2OD13M{Cgcm0> MXmyN|Y6QTZ3NR?=
T98G  NVn0bph[SXCxcITvd4l{KEG|c3H5 M2T5OVExOC9{NUCgcm0> MV:2JIg> M3HMToVvcGGwY3XzJJJi\GmjdHnvck1qdmS3Y3XkJINmdGxia3nscIlv\w>? M{G0SlIyQTl{N{mz
A549 M3v6bGFxd3C2b4Ppd{BCe3OjeR?= NIjFTmwzODBibl2= M2XjNFEhcA>? MnjRdoFlcW:|ZX7zbZRqgmW|IF7TR2xEKGOnbHzzJIlvKGFicEWzMYRmeGWwZHXueEBu[W6wZYK= Mn7qNlE4QTlyM{O=
H460 NHfnOHVCeG:ydH;zbZMhSXO|YYm= MlnINlAxKG6P MVixJIg> M{PjepJi\Gmxc3Xud4l1cXqnczDOV2NNSyClZXzsd{BqdiCjIIC1N{1l\XCnbnTlcpQhdWGwbnXy MWeyNVc6QTB|Mx?=
H1299 MVHBdI9xfG:|aYOgRZN{[Xl? NHnvWXczODBibl2= NXfMV|VrOSCq MUXyZYRqd3OnboPpeIl7\XNiTmPDUGMh[2WubIOgbY4h[SCyNUOt[IVx\W6mZX70JI1idm6nch?= M2P1W|IyPzl7MEOz
Calu-6  MmfGRZBweHSxc3nzJGF{e2G7 NH7MVYkzODBibl2= MV6xJIg> MU\yZYRqd3OnboPpeIl7\XNiTmPDUGMh[2WubIOgbY4h[SCyNUOt[IVx\W6mZX70JI1idm6nch?= NIfqRnMzOTd7OUCzNy=>
WiDr MXzLbY5ie2ViQYPzZZl{ NUHQeJI1OTBvMUCwNFAhdk1? MXK4JIg> M1XmXYlvcGmkaYTzJJBpd3OyaH;yfYxifGmxbjDv[kBETEN{IHH0JHR6ejF3IIfpeIgh[W5iRVO1NOKhfmGudXWgc4YhQDVibn3vcE9NKHC{ZYTy[YF1\WRid3n0bEBo\W2laYThZolv\Q>? Ml\RNVk5QDd3NEW=

... 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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