Adavosertib

Protein target name:

WEE1

Mechanism of action:

Inhibitor, ATP competitive

Recommended Concentration for use in cells:

~~30-100 nM or 300 nM (alone)~~

Reviewer suggested Concentration for use in cells:

300-1000 nM

Probe Availability

MedChemExpress

Selleck Chemicals

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

Ser/Thr Protein Kinase

HUGO ID:

HGNC:12761

Entrez gene ID:

7465

UNIPROT ID:

P30291

Target alias:

WEE1A; WEE1hu

Probe Details

Chemical Probes Portal ID:

CPP2066

Probe alias:

MK-1775

PubChem CID:

24856436

ChEMBL ID:

CHEMBL1976040

SMILES string:

O=C1N(N(C2=NC(NC3=CC=C(C=C3)N4CCN(CC4)C)=NC=C21)C5=NC(C(O)(C)C)=CC=C5)CC=C

InChi Key:

BKWJAKQVGHWELA-UHFFFAOYSA-N

PAINs evaluation:

PAINS-Free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

5.2 nM

Potency assay:

Radioactive in vitro Kinase assay

Structure-activity relationship:

Off target activity

Probe Selectivity in Vitro:

Among 223 kinases in the Upstate Kinase Profiler panel, only 8 kinases were inhibited by >80% @ 1 μM MK-1775. The IC50 values determined for these eight kinases indicate that MK-1775 is 10-fold less potent against seven of these kinases relative to Wee1 and 2- to 3-fold less potent against Yes (IC50 was 14 nmol/L). MK-1775 shows >100-fold selectivity over human Myt 1, another kinase that suppresses CDC2 by a phosphorylation at an alternative site

In cell validation

On target activity in cells

Potency in cells:

EC50

49 nM (alone), 85 nM (in combination

Potency assay (cells):

p-CDC2 and pHH3 Assays (calorimetric ELISA)

In vivo validation

Organism:

nude rats bearing WiDr (human colorectal) tumors

Dose:

5, 10, or 20 mg/kgReviewer suggest: 20 and 30 mg/Kg

Route of delivery:

Oral

Primary Reference

Reference (doi):

10.1158/1535-7163.MCT-09-0463

Reference (PMID):

19887545

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

MK-1775 (Adavosertib) is a potent inhibitor of Wee1 and Wee2, with off target biochemical and cellular activity on a number of other kinases, including polo-like kinase-1 (PLK1).

Dec 14 2020 - 8:42am

Adavosertib unarguably displays both potent WEE1 kinase affinity and a strong phenotype when in combination with common chemotherapies in vivo. However there are studies since published (10.1021/acschembio.7b00147, 10.1021/acs.jmedchem.7b00996) that demonstrate that this molecule has potent binding affinity for both WEE2 and PLK1. PLK1 is directly upstream of WEE1, acts as a negative regulator of active WEE1 amongst a myriad of other signalling roles and it’s inhibition by adavosertib likely plays a role (in addition to WEE1 inhibition) in this molecule’s cellular effects. Therefore, whilst this compound shows good broad selectivity across the kinome, it does have some specific liabilities that undermine its use as a chemical probe for furthering the understanding and consequences of WEE1 perturbation alone or even WEE kinases more broadly.

Jan 7 2021 - 11:54am

Adavosertib

Probe Availability

Probe Information

Target Details

WEE1A; WEE1hu

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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Adavosertib

Probe Availability

Probe Information

Target Details

WEE1A; WEE1hu

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?