Adavosertib (MK-1775)

Synonyms: AZD1775

Adavosertib (MK-1775, AZD1775) 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.

Adavosertib (MK-1775) Chemical Structure

Adavosertib (MK-1775) Chemical Structure

CAS No. 955365-80-7

Purity & Quality Control

Adavosertib (MK-1775) Related Products

Signaling Pathway

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
ASPC-1 Growth Inhibition Assay IC50=13.2 ± 1.1 μM 25458954
BxPC-3 Growth Inhibition Assay IC50=0.8 ± 0.03 μM 25458954
CFPAC-1 Growth Inhibition Assay IC50=3.3 ± 0.2 μM 25458954
HPAC Growth Inhibition Assay IC50=0.5 ± 0.01 μM 25458954
MIAPaCa-2 Growth Inhibition Assay IC50=0.5 ± 0.05 μM 25458954
PANC-1 Growth Inhibition Assay IC50=10.6 ± 1.1 μM 25458954
SK-N-BE (2) Growth Inhibition Assay IC50=2.4 ± 0.3 μM 25308916
SK-N-BE (2), PAN→MK Growth Inhibition Assay IC50=26.6 ± 9.6 μM 25308916
SK-N-BE (2), MK→PAN Growth Inhibition Assay IC50=2.4 ± 0.3 μM 25308916
SK-N-AS Growth Inhibition Assay IC50=0.50 ± 0.02 μM 25308916
SK-N-DZ Growth Inhibition Assay IC50=0.36 ± 0.01 μM 25308916
SK-N-AS Apoptosis Assay 500 nM 48 h induces cell apoptosis 25308916
SK-N-DZ Apoptosis Assay 500 nM 48 h induces cell apoptosis 25308916
THP-1 Growth Inhibition Assay 125/250/500 nM 48 h increases cell death in a concentration-dependent manner 25084614
MV4-11 Growth Inhibition Assay 125/250/500 nM 48 h increases cell death in a concentration-dependent manner 25084614
U937 Growth Inhibition Assay 125/250/500 nM 48 h increases cell death in a concentration-dependent manner 25084614
HL-60 Growth Inhibition Assay 125/250/500 nM 48 h increases cell death in a concentration-dependent manner 25084614
OCI-AML3 Growth Inhibition Assay 125/250/500 nM 48 h increases cell death in a concentration-dependent manner 25084614
MOLM-13 Growth Inhibition Assay 125/250/500 nM 48 h increases cell death in a concentration-dependent manner 25084614
CMK Cell Viability Assay 10-10000 nM 72 h reduces cell vialibity in a concentration-dependent manner 24962331
CMY Cell Viability Assay 10-10000 nM 72 h reduces cell vialibity in a concentration-dependent manner 24962331
Dayo Growth Inhibition Assay IC50=150 nM 24661910
UW228 Growth Inhibition Assay IC50=232 nM 24661910
IST-MES1 Cell Viability Assay 150/250 nM 72 h enhances the cisplatin cytotoxic effect in a concentration-dependent manner 24365782
IST-MES2 Cell Viability Assay 150/250 nM 72 h enhances the cisplatin cytotoxic effect in a concentration-dependent manner 24365782
REN Cell Viability Assay 150/250 nM 72 h enhances the cisplatin cytotoxic effect in a concentration-dependent manner 24365782
NCI-H2452 Cell Viability Assay 150/250 nM 72 h enhances the cisplatin cytotoxic effect in a concentration-dependent manner 24365782
MSTO-211H Cell Viability Assay 150/250 nM 72 h enhances the cisplatin cytotoxic effect in a concentration-dependent manner 24365782
NCI-H2052 Cell Viability Assay 150/250 nM 72 h enhances the cisplatin cytotoxic effect in a concentration-dependent manner 24365782
WEE1 Growth Inhibition Assay IC50=5.2 nM 23699655
CDC2 Growth Inhibition Assay IC50>1000 nM 23699655
CDK7 Growth Inhibition Assay IC50>1000 nM 23699655
MYT1 Growth Inhibition Assay IC50=530 nM 23699655
T98G  Apoptosis Assay 100/250 nM 6 h enhances radiation-induced cell killing 21992793
A549 Apoptosis Assay 200 nM 1 h radiosensitizes NSCLC cells in a p53-dependent manner 21799033
H460 Apoptosis Assay 200 nM 1 h radiosensitizes NSCLC cells in a p53-dependent manner 21799033
H1299 Apoptosis Assay 200 nM 1 h radiosensitizes NSCLC cells in a p53-dependent manner 21799033
Calu-6  Apoptosis Assay 200 nM 1 h radiosensitizes NSCLC cells in a p53-dependent manner 21799033
WiDr Kinase Assays 10-10000 nM 8 h inhibits phosphorylation of CDC2 at Tyr15 with an EC50 value of 85 nmol/L pretreated with gemcitabine 19887545
Function assay Expi293F Binding affinity to recombinant human full-length N-terminal His8-tagged Wee1 (1 to 646 residues) expressed in human Expi293F cells assessed as dessociation constant by quantitative real-time PCR method, Kd = 0.0032 μM. 28792760
Function assay Expi293F Binding affinity to recombinant human full-length N-terminal His8-tagged Wee2 (1 to 567 residues) expressed in human Expi293F cells assessed as dessociation constant by quantitative real-time PCR method, Kd = 0.0039 μM. 28792760
Antiproliferative assay MDA-MB-231 72 hrs Antiproliferative activity against human MDA-MB-231 cells measured after 72 hrs by CellTiter-Blue assay, IC50 = 0.26 μM. 28792760
Antiproliferative assay HEK293T 72 hrs Antiproliferative activity against HEK293T cells measured after 72 hrs by CellTiter-Blue assay, IC50 = 0.29 μM. 28792760
Antiproliferative assay MM1S 72 hrs Antiproliferative activity against human MM1S cells measured after 72 hrs by CellTiter-Blue assay, IC50 = 0.31 μM. 28792760
Function assay HEK293 1 hr Inhibition of human full length PKMYT1 expressed in HEK293 cells using EFS (247 to 259 residues) as substrate after 1 hr by fluorescence polarization immunoasay, Ki = 0.47 μM. 29941193
Function assay HEK293 1 hr Inhibition of human full length PKMYT1 expressed in HEK293 cells using EFS (247 to 259 residues) as substrate after 1 hr by fluorescence polarization immunoasay, IC50 = 4.94 μM. 29941193
Function assay MDA-MB-231 0.1 to 10 uM 6 hrs Inhibition of Wee1 in human MDA-MB-231 cells assessed as decrease in CDK1 phosphorylation at Tyr 15 at 0.1 to 10 uM after 6 hrs by Western blot method 28792760
Function assay HEK293T 0.1 to 10 uM 6 hrs Inhibition of Wee1 in HEK293T cells assessed as decrease in CDK1 phosphorylation at Tyr15 at 0.1 to 10 uM after 6 hrs by Western blot method 28792760
Function assay HEK293T 0.1 to 10 uM 6 hrs Inhibition of PLK1 in HEK293T cells assessed as decrease in TCTP phosphorylation at 0.1 to 10 uM after 6 hrs by Western blot method 28792760
Function assay MDA-MB-23 0.1 to 10 uM 6 hrs Inhibition of PLK1 in human MDA-MB-23 cells assessed as decrease in TCTP phosphorylation at 0.1 to 10 uM after 6 hrs by Western blot method 28792760
qHTS assay TC32 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells 29435139
qHTS assay U-2 OS qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells 29435139
qHTS assay A673 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells 29435139
qHTS assay DAOY qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells 29435139
qHTS assay Saos-2 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells 29435139
qHTS assay BT-37 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells 29435139
qHTS assay RD qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells 29435139
qHTS assay SK-N-SH qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells 29435139
qHTS assay BT-12 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells 29435139
qHTS assay NB1643 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells 29435139
qHTS assay OHS-50 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells 29435139
qHTS assay BT-12 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-12 cells 29435139
qHTS assay DAOY qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for DAOY cells 29435139
qHTS assay SK-N-SH qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-SH cells 29435139
qHTS assay Rh41 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells 29435139
qHTS assay A673 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for A673 cells) 29435139
qHTS assay MG 63 (6-TG R) qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for MG 63 (6-TG R) cells 29435139
qHTS assay U-2 OS qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for U-2 OS cells 29435139
qHTS assay OHS-50 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for OHS-50 cells 29435139
qHTS assay Rh41 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh41 cells 29435139
qHTS assay RD qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for RD cells 29435139
qHTS assay SJ-GBM2 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells 29435139
qHTS assay SK-N-MC qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells 29435139
qHTS assay NB-EBc1 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells 29435139
qHTS assay LAN-5 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells 29435139
qHTS assay Rh18 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells 29435139
qHTS assay SJ-GBM2 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SJ-GBM2 cells 29435139
qHTS assay Saos-2 qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Saos-2 cells 29435139
Click to View More Cell Line Experimental Data

Biological Activity

Description Adavosertib (MK-1775, AZD1775) 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
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 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]

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

Cells are treated 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.

Experimental Result Images Methods Biomarkers Images PMID
Western blot p-Cdk1(Y15) / Cdk1 p-KAP1(S824) / p-Chk2(T68) / p-Chk1(S345) PARP / CF-PARP / pH3(S10) / p-CDC25c(S216) / p-CDK2(Y15) WEE1 25609063
Immunofluorescence tubulin / p-HH3(S10) γH2AX Cleaved caspase-3 / pH3 30755439
Growth inhibition assay Cell viability IC50 25458954
In Vivo
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]

Animal Research Animal Models Immunodeficient nude rats (F344/NJcl-rnu) bearing WiDr, HeLa-luc, or TOV21G-shp53 tumors
Dosages ~20 mg/kg/day
Administration Orally
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT03253679 Completed
Advanced Malignant Solid Neoplasm|Refractory Malignant Solid Neoplasm
National Cancer Institute (NCI)
January 16 2019 Phase 2
NCT03668340 Active not recruiting
Uterine Cancer
Dana-Farber Cancer Institute|AstraZeneca
October 22 2018 Phase 2
NCT03028766 Completed
Hypopharynx Squamous Cell Carcinoma|Oral Cavity Squamous Cell Carcinoma|Larynx Cancer
University of Birmingham|AstraZeneca|Cancer Research UK
June 22 2017 Phase 1

Chemical Information & Solubility

Molecular Weight 500.6 Formula

C27H32N8O2

CAS No. 955365-80-7 SDF Download Adavosertib (MK-1775) SDF
Smiles CC(C)(C1=NC(=CC=C1)N2C3=NC(=NC=C3C(=O)N2CC=C)NC4=CC=C(C=C4)N5CCN(CC5)C)O
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 100 mg/mL ( (199.76 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble


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In vivo
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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

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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.

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