Adavosertib

Adavosertib : ATP competitive inhibitor of WEE1

Structure

SERP Rating

In Cells

(2 ratings)

In Model Organisms

(2 ratings)

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Probe Adavosertib is in the process of SERP review.

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Information

WEE1

Inhibitor, ATP competitive

~~30-100 nM or 300 nM (alone)~~
Reviewer recommended concentration: 300-1000 nM

Probe Availability:

In Vitro Validations

Uniprot ID: P30291

Target Class: Protein kinase

Target SubClass: Ser/Thr Protein Kinase

Potency: IC50

Potency Value: 5.2 nM

Potency Assay: Radioactive in vitro Kinase assay

PDB ID for probe-target interaction (3D structure): --

Structure-activity relationship: no

Target aliases:

Wee1-like protein kinase, WEE1, WEE1_HUMAN, WEE1hu ...

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

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

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP 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).

(last updated: 10 Dec 2020 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

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.

(last updated: 21 Dec 2020 )