WZ4002

Covalent Inhibitor, Mutant Selective of EGFR

Structure

Information

Protein target names: EGFR

Mechanism of action: Covalent Inhibitor, Mutant Selective

Recommended in-cell concentration:
up to 100 nM
Primary References:

In Vitro Validations

Uniprot ID: P00533
Target Class: Protein kinase
Target SubClass: RTK
Potency: KD
Potency Value: 14 WT, 2.2 T790M, 1.5 L858R, 0.13 L858R/T790M nM
Potency Assay: EGFR kinase assays
PDB ID for probe-target interaction (3D structure): 3IKA
Structure-activity relationship: yes
Target aliases:
Epidermal growth factor receptor, HER1, ERBB1, ERB ...

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

Comments:

WZ4002 is a covalent inhibitor of EGFR variants carrying the T790M mutant. The cmpd shows roughly a 10fold selectivity window vs. EGFR wt in cellular studies which also translates into in vivo studies. The data set is limited and does not allow conclusions about selectivity against other kinases. Biochemical selectivity data show off-target activity against certain kinases with a cysteine in a position analogous to C797, e.g. BMX, SNARK, BTK. However, for covalent inhibitors stationary IC50 values do not allow to accurately assess selectivity. For BMX it is shown that the cellular IC50 is within a 10fold range compared to cellular EGFR T790M potency. No data are provided about potential targets beyond kinases. The provided data set does not fulfil quality criteria as would be expected in 2021 for a covalent inhibitor, e.g. a broader assessment of the cellular interactome by a MS proteomics study. Therefore, WZ4002 may only be used for specific cellular studies on EGFR T790M but findings should be confirmed with a second chemically differentiated inhibitor.

(last updated: 2 Mar 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

Comments:

This is a covalent inhibitor of various EGFR mutants and is potent in biochemical and cellular assays. Depending on the cell line used, the selectivity for EGFR over other cysteine containing kinases, such as ERBB2 and BTK, could start to overlap such that interpretation of the data would benefit from additional inhibitors with different profiles.

(last updated: 2 Mar 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

Comments:

WZ4002 is identified as a covalent inhibitor potent against EGFR mutants including both primary activating mutations (e.g., L858R, ΔE746-A750) and resistant mutation T790M (e.g., L858R/T790M,  ΔE746-A750/T790M double mutants). By design, it is rather weak against EGFR WT. If the intended research is on EGFR wild type, pan-EGFR inhibitor such as afatinib would be more suitable. If the intended research is on EGFR mutants other than those discussed in the primary paper, inhibitor potency needs to be determined. Given its potency requires covalent modification of Cys797, any EGFR kinase construct or cell line bearing C797X mutation would be insensitive. Furthermore, its kinome selectivity is good but not perfect, therefore use of multiple probes against the same target, such as Osimertinib/AZD9291, or counter-screen with selective inhibitors against BTK, ITK, or ERBB4 would be prudent.

(last updated: 12 Mar 2021 )