Adavosertib (MK-1775)

Catalog No.S1525

Adavosertib (MK-1775) Chemical Structure

Molecular Weight(MW): 500.6

MK-1775 is a potent and selective Wee1 inhibitor with IC50 of 5.2 nM in a cell-free assay; hinders G2 DNA damage checkpoint. Phase 2.

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Cited by 33 Publications

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Biological Activity

Description MK-1775 is a potent and selective Wee1 inhibitor with IC50 of 5.2 nM in a cell-free assay; hinders G2 DNA damage checkpoint. Phase 2.
Features The first reported Wee1 inhibitor.
Targets
Wee1 [1]
(Cell-free assay)
5.2 nM
In vitro

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 Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
ASPC-1 NEHMSYFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MonyTWM2OD1zMz6yJOKyKDFwMTFOwG0> NFTvVnIzPTR3OEm1OC=>
BxPC-3 M3v4U2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFXG[mJKSzVyPUCuPEDDuSByLkCzJO69VQ>? NUjTWoF3OjV2NUi5OVQ>
CFPAC-1 MYjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NXzydIluUUN3ME2zMlMhyrFiMD6yJO69VQ>? NWThd2toOjV2NUi5OVQ>
HPAC NF3sWWFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXTJR|UxRTBwNTFCtUAxNjBzIN88US=> MmmwNlU1PTh7NUS=
MIAPaCa-2 M{\sS2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1u5cGlEPTB;MD61JOKyKDBwMEWg{txO MVqyOVQ2QDl3NB?=
PANC-1 MWTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3PKe2lEPTB;MUCuOkDDuSBzLkGg{txO MWCyOVQ2QDl3NB?=
SK-N-BE (2) MYrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1vzWWlEPTB;Mj605qCKyrIkgJmwMlMh|ryP NVLVelBlOjV|MEi5NVY>
SK-N-BE (2), PAN→MK NVu2WJM3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUjJR|UxRTJ4LkdihKnDueLCiUmuOkDPxE1? NYDjb4dVOjV|MEi5NVY>
SK-N-BE (2), MK→PAN M4rKTGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NED5S4NKSzVyPUKuOQKBkcLz4pEJNE4{KM7:TR?= Ml65NlU{ODh7MU[=
SK-N-AS M3\IR2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MXHJR|UxRTBwNUFihKnDueLCiUCuNFIh|ryP MoXUNlU{ODh7MU[=
SK-N-DZ NVjiSZJrT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUjJR|UxRTBwM{dihKnDueLCiUCuNFEh|ryP MoXzNlU{ODh7MU[=
SK-N-AS MkfZRZBweHSxc3nzJGF{e2G7 Mn7aOVAxKG6P M4rXZlQ5KGh? MVjpcoR2[2W|IHPlcIwh[XCxcITvd4l{ M4HETVI2OzB6OUG2
SK-N-DZ MoTzRZBweHSxc3nzJGF{e2G7 MYO1NFAhdk1? MVG0PEBp NVvLbIhScW6mdXPld{Bk\WyuIHHwc5B1d3Orcx?= NH;He4ozPTNyOEmxOi=>
THP-1 MXzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NG\J[|kyOjVxMkWwM|UxOCCwTR?= NGX4eJk1QCCq Ml3tbY5kemWjc3XzJINmdGxiZHXheIghcW5iYTDjc45k\W62cnH0bY9vNWSncHXu[IVvfCCvYX7u[ZI> MXeyOVA5PDZzNB?=
MV4-11 NXnUS|ljT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUT5VVNKOTJ3L{K1NE82ODBibl2= Mk\YOFghcA>? MVrpcoNz\WG|ZYOgZ4VtdCCmZXH0bEBqdiCjIHPvcoNmdnS{YYTpc44u\GWyZX7k[Y51KG2jbn7ldi=> M1nwclI2ODh2NkG0
U937 NWe2eYFST3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M371eFEzPS9{NUCvOVAxKG6P NV;XbndNPDhiaB?= NFv5bZNqdmO{ZXHz[ZMh[2WubDDk[YF1cCCrbjDhJINwdmOnboTyZZRqd25vZHXw[Y5l\W62IH3hco5meg>? MY[yOVA5PDZzNB?=
HL-60 NEHDO3dIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MkHINVI2NzJ3MD:1NFAhdk1? MVy0PEBp NGr2NoNqdmO{ZXHz[ZMh[2WubDDk[YF1cCCrbjDhJINwdmOnboTyZZRqd25vZHXw[Y5l\W62IH3hco5meg>? M{nMe|I2ODh2NkG0
OCI-AML3 M4L0N2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NVrPRZpzOTJ3L{K1NE82ODBibl2= MknaOFghcA>? MV7pcoNz\WG|ZYOgZ4VtdCCmZXH0bEBqdiCjIHPvcoNmdnS{YYTpc44u\GWyZX7k[Y51KG2jbn7ldi=> Mm\XNlUxQDR4MUS=
MOLM-13 MYPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MWexNlUwOjVyL{WwNEBvVQ>? NEC5VZA1QCCq M4WyTIlv[3KnYYPld{Bk\WyuIHTlZZRpKGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz MYiyOVA5PDZzNB?=
CMK M1rKTmNmdGxiVnnhZoltcXS7IFHzd4F6 NEPw[G8yOC1zMECwNEBvVQ>? MXG3NkBp NVPOdYRHemWmdXPld{Bk\WyuII\pZYxq[mm2eTDpckBiKGOxbnPlcpRz[XSrb36t[IVx\W6mZX70JI1idm6nch?= NETmdIQzPDl4MkOzNS=>
CMY M1;vT2NmdGxiVnnhZoltcXS7IFHzd4F6 MYexNE0yODByMDDuUS=> Mo\WO|IhcA>? MUPy[YR2[2W|IHPlcIwhfmmjbHnibZR6KGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz NHS3SpMzPDl4MkOzNS=>
Dayo MVTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1XWT2lEPTB;MUWwJI5O M4DuW|I1PjZzOUGw
UW228 NGrN[VhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M{TwfWlEPTB;MkOyJI5O NVGyRYw6OjR4NkG5NVA>
IST-MES1 NILwU4xE\WyuIG\pZYJqdGm2eTDBd5NigQ>? MojENVUxNzJ3MDDuUS=> NW\rOm1wPzJiaB?= M4TWPIVvcGGwY3XzJJRp\SClaYPwcIF1cW5iY4n0c5RwgGmlIHXm[oVkfCCrbjDhJINwdmOnboTyZZRqd25vZHXw[Y5l\W62IH3hco5meg>? NET5U3YzPDN4NUe4Ni=>
IST-MES2 MlHqR4VtdCCYaXHibYxqfHliQYPzZZk> M3\DcFE2OC9{NUCgcm0> NVvzVpBmPzJiaB?= NGX1OodmdmijbnPld{B1cGViY3nzdIxifGmwIHP5eI91d3irYzDl[oZm[3RiaX6gZUBkd26lZX70doF1cW:wLXTldIVv\GWwdDDtZY5v\XJ? MXSyOFM3PTd6Mh?=
REN MWDD[YxtKF[rYXLpcIl1gSCDc4PhfS=> NHu2VHoyPTBxMkWwJI5O MkKzO|IhcA>? NVTQ[WlK\W6qYX7j[ZMhfGinIHPpd5Bt[XSrbjDjfZRwfG:6aXOg[YZn\WO2IHnuJIEh[2:wY3XueJJifGmxbj3k[ZBmdmSnboSgcYFvdmW{ Mle4NlQ{PjV5OEK=
NCI-H2452 M3\LOGNmdGxiVnnhZoltcXS7IFHzd4F6 M3\PUlE2OC9{NUCgcm0> MmPIO|IhcA>? Mlfj[Y5p[W6lZYOgeIhmKGOrc4DsZZRqdiCleYTveI95cWNiZX\m[YN1KGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz M1PINFI1OzZ3N{iy
MSTO-211H NX3K[2t3S2WubDDWbYFjcWyrdImgRZN{[Xl? NX7tcVlIOTVyL{K1NEBvVQ>? M4LvT|czKGh? MVTlcohidmOnczD0bIUh[2m|cHzheIlvKGO7dH;0c5hq[yCnZn\lZ5QhcW5iYTDjc45k\W62cnH0bY9vNWSncHXu[IVvfCCvYX7u[ZI> NFHQe3czPDN4NUe4Ni=>
NCI-H2052 MUPD[YxtKF[rYXLpcIl1gSCDc4PhfS=> M{jkeVE2OC9{NUCgcm0> MmK3O|IhcA>? Mkjt[Y5p[W6lZYOgeIhmKGOrc4DsZZRqdiCleYTveI95cWNiZX\m[YN1KGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz NVSxXFk3OjR|NkW3PFI>
WEE1 MV7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NEjJSZNKSzVyPUWuNkBvVQ>? MXyyN|Y6QTZ3NR?=
CDC2 M1fremdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUfGOJEzUUN3MP-8olExODBibl2= MmrINlM3QTl4NUW=
CDK7 MWrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MUTJR|Ux97zgMUCwNEBvVQ>? MoDpNlM3QTl4NUW=
MYT1 NVHW[mo{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWLYZmtlUUN3ME21N|Ahdk1? M2rjWFI{Pjl7NkW1
T98G  M13l[mFxd3C2b4Ppd{BCe3OjeR?= NV33VJFCOTByL{K1NEBvVQ>? MUe2JIg> MXvlcohidmOnczDyZYRq[XSrb36tbY5lfWOnZDDj[YxtKGurbHzpcoc> NFq1OogzOTl7Mke5Ny=>
A549 M3XkeWFxd3C2b4Ppd{BCe3OjeR?= MWqyNFAhdk1? MoT2NUBp Ml;vdoFlcW:|ZX7zbZRqgmW|IF7TR2xEKGOnbHzzJIlvKGFicEWzMYRmeGWwZHXueEBu[W6wZYK= Mn;nNlE4QTlyM{O=
H460 M1\HcWFxd3C2b4Ppd{BCe3OjeR?= NWfaemgzOjByIH7N M2PRb|EhcA>? M1T2XZJi\Gmxc3Xud4l1cXqnczDOV2NNSyClZXzsd{BqdiCjIIC1N{1l\XCnbnTlcpQhdWGwbnXy MV[yNVc6QTB|Mx?=
H1299 M4juemFxd3C2b4Ppd{BCe3OjeR?= NHnXPG0zODBibl2= NITofpEyKGh? MnfEdoFlcW:|ZX7zbZRqgmW|IF7TR2xEKGOnbHzzJIlvKGFicEWzMYRmeGWwZHXueEBu[W6wZYK= NF:1WmgzOTd7OUCzNy=>
Calu-6  MVTBdI9xfG:|aYOgRZN{[Xl? NHHCZZAzODBibl2= MX6xJIg> NUDYdYlvemGmaX;z[Y5{cXSrenXzJG5US0yFIHPlcIx{KGmwIHGgdFU{NWSncHXu[IVvfCCvYX7u[ZI> MYKyNVc6QTB|Mx?=
WiDr NF\BeJdMcW6jc3WgRZN{[Xm| M2nT[VExNTFyMECwJI5O NHj5S5c5KGh? NUX5O2V[cW6qaXLpeJMheGixc4Doc5J6dGG2aX;uJI9nKEOGQ{KgZZQhXHm{MUWge4l1cCCjbjDFR|UxyqC4YXz1[UBw\iB6NTDucY9tN0xicILleJJm[XSnZDD3bZRpKGenbXPpeIFjcW6n Mn;XNVk5QDd3NEW=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
p-Cdk1(Y15) / Cdk1; 

PubMed: 25609063     


The impact of a 24 hour pre-treatment of MK-1775 on p-Cdk1 was assessed by western blotting. Because of low basal phosphorylation, GBM22 was irradiated (RT) with 10 Gy.

p-KAP1(S824) / p-Chk2(T68) / p-Chk1(S345); 

PubMed: 25609063     


Western blot evaluation of GBM6 and GBM22 short-term explant cultures 24 hours after treatment with either MK-1775 or TMZ or the combination. 

PARP / CF-PARP / pH3(S10) / p-CDC25c(S216) / p-CDK2(Y15); 

PubMed: 25458954     


Pancreatic cancer cells were treated with vehicle control or 500 nM MK-1775 for 48 h. Whole cell lysates were subjected to Western blotting and probed with anti-PARP, -p-H3, -γH2AX, -p-CHK1, -CHK1, -p-CDC25C, -p-CDK1, - CDK1, -p-CDK2, -CDK2, or -β-actin antibody.

WEE1; 

PubMed: 27616351     


MIA PaCa2, PANC-1, Hs 766T, Capan-1 and PL11 cells were treated with MK-1775 (400 nM/L) and/or MMC (150 nM/L) for 24 hours. Whole cell lysates were prepared using RIPA and western blot was performed to assess the protein expression of WEE1 (90 kDa), pCDK1(y15) (34 kDa), CDK1 (34 kDa) and GAPDH (36 kDa) as loading control. 

25609063 25458954 27616351
Immunofluorescence
tubulin / p-HH3(S10); 

PubMed: 30755439     


FaDu and UNC7 cells were treated with adavosertib (500 nM), alisertib (250 nM), or adavosertib + alisertib for 24 hours and followed by immunofluorescent staining with anti-tubulin (Green) and anti-pHH3 (S10; Red). Nucleus was stained with DAPI. (A) Representative images of mitotic cells were captured by confocal microscopy. Scale bar: 10 µm.

γH2AX; 

PubMed: 25609063     


A) γH2AX foci formation in GBM6 and GBM22 were assessed 24 h after a single treatment of 300 nM MK-1775. 

Cleaved caspase-3 / pH3; 

PubMed: 27616351     


MIA PaCa2 cells were treated and dual stained with pH3 to observe mitotic entry; and cleaved caspase 3 (CL-CSP3) to observe caspase 3 activity.

30755439 25609063 27616351
Growth inhibition assay
Cell viability; 

PubMed: 25458954     


Pancreatic cancer cell lines were cultured in 96-well plates at 37℃ for 48 h in complete medium with variable concentrations of MK-1775 and viable cell numbers were determined using MTT reagent and a microplate reader. The data are presented as means ± standard errors from at least 3 independent experiments.

IC50; 

PubMed: 25084614     


AML cell lines were cultured for 72 h in complete medium with variable concentrations of MK-1775 (MK) and viable cell numbers were determined using MTT assays. IC50 values were calculated as drug concentration necessary to inhibit 50% growth compared to untreated control cells.

25458954 25084614
In vivo 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]

Protocol

Kinase Assay:

[1]

+ Expand

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.
Cell Research:

[1]

+ Expand
  • Cell lines: WiDr, NCI-H1299, TOV21G, and HeLa
  • Concentrations: Dissolved in DMSO, final concentrations ~10 μM
  • Incubation Time: 24 hours
  • Method:

    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.


    (Only for Reference)
Animal Research:

[1]

+ Expand
  • Animal Models: Immunodeficient nude rats (F344/NJcl-rnu) bearing WiDr, HeLa-luc, or TOV21G-shp53 tumors
  • Formulation: Prepared in a vehicle of 0.5% methylcellulose solution
  • Dosages: ~20 mg/kg/day
  • Administration: Orally
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 80 mg/mL (159.8 mM)
Ethanol 10 mg/mL (19.97 mM)
Water 0.0001 mg/mL (0.0 mM)
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
2% DMSO+30% PEG 300+5% Tween 80+ddH2O
For best results, use promptly after mixing.
5mg/mL

* 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 Information

Molecular Weight 500.6
Formula

C27H32N8O2

CAS No. 955365-80-7
Storage powder
in solvent
Synonyms N/A

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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.

Handling Instructions

Tel: +1-832-582-8158 Ext:3

If you have any other enquiries, please leave a message.

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Frequently Asked Questions

  • Question 1:

    How to prepare MK1775 methylcellulose solution? and how to prepare methylcellulose itself? Once make the MK1775 methylcellulose solution, how should i keep it?

  • Answer:

    MK1775 in 0.5% methylcellulose is a suspension or emulsion, and it is ok to treat mice orally. It is recommended to dissolve methylcellulose in saline. It will take some time to dissolve methylcellulose, and you can vortex it for a while. The MK1775 methylcellulose solution can be stored at 4°C for a week.

Wee1 Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID