Adavosertib (MK-1775)

Catalog No.S1525 Batch:S152507

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Technical Data

Formula

C27H32N8O2
Molecular Weight 500.6 CAS No. 955365-80-7
Solubility (25°C)* In vitro DMSO 100 mg/mL (199.76 mM)
Ethanol 10 mg/mL (19.97 mM)
Water Insoluble
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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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.
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]
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]
Features The first reported Wee1 inhibitor.

Protocol (from reference)

Kinase Assay:

[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.
Cell Assay:

[1]
  • 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.
Animal Study:

[1]
  • Animal Models

    Immunodeficient nude rats (F344/NJcl-rnu) bearing WiDr, HeLa-luc, or TOV21G-shp53 tumors

  • Dosages

    ~20 mg/kg/day

  • Administration

    Orally

Customer Product Validation

Data from [Data independently produced by J Hematol Oncol, 2014, 7:53]

Data from [Data independently produced by Oncol Rep, 2014, 32(5), 1991-8]

Data from [Data independently produced by Endocrinology, 2013, 154(9), 3219-27]

Data from [Data independently produced by PLoS One, 2013, 8(3), e57523]

Selleck's Adavosertib (MK-1775) has been cited by 229 publications

Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation [ Nat Commun, 2024, 15(1):2089] PubMed: 38453961
ATR limits Rad18-mediated PCNA monoubiquitination to preserve replication fork and telomerase-independent telomere stability [ EMBO J, 2024, 43(7):1301-1324] PubMed: 38467834
The Golgi checkpoint: Golgi unlinking during G2 is necessary for spindle formation and cytokinesis [ Life Sci Alliance, 2024, 7(5)e202302469] PubMed: 38479814
The SUMO-NIP45 pathway processes toxic DNA catenanes to prevent mitotic failure [ Nat Struct Mol Biol, 2023, 10.1038/s41594-023-01045-0] PubMed: 37474739
Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer [ Nat Commun, 2023, 14(1):6332] PubMed: 37816716
Mild replication stress causes premature centriole disengagement via a sub-critical Plk1 activity under the control of ATR-Chk1 [ Nat Commun, 2023, 14(1):6088] PubMed: 37773176
Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma [ EMBO Mol Med, 2023, e16863.] PubMed: 36779660
SOX2 expression in prostate cancer drives resistance to nuclear hormone receptor signaling inhibition through the WEE1/CDK1 signaling axis [ Cancer Lett, 2023, 565:216209] PubMed: 37169162
Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth [ Cell Death Dis, 2023, 10.1038/s41419-023-06167-3] PubMed: 37758718
Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth [ Cell Death Dis, 2023, 14(9):638] PubMed: 37758718

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