NR162

NR162 : Inhibitor of CASK

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(0 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

CASK

Inhibitor

~~up to 10 uM~~
Reviewer recommended concentration: up to 3 uM

Additional Data

SGC Chemical Probe Collection

Probe Availability:

MedChemExpress

In Vitro Validations

Uniprot ID: O14936

Target Class: Kinase

Target SubClass: CAMK

Potency: Kd

Potency Value: 22 nM

Potency Assay: ITC

PDB ID for probe-target interaction (3D structure): 7OAK

Target aliases:

Peripheral plasma membrane protein CASK, LIN2, CAS ...

DOI Reference: 10.1021/acs.jmedchem.1c00845

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

NR162 has been shown to be selective in a DiscoverX KINOMEScan at 1 µM. The closest off-target was TYRO3 (IC50 = 3.8 µM) and ERBB3 (IC50 = 18.2 µM) as determined by follow-up NanoBRET assay.

Probe Selectivity in Cell:

In the NCI-60 screen, which is a human tumor cell line screen, NR162 showed no significant cell toxicity as well as growth inhibition. It was tested in a single high dose of 10 µM in the full NCI-60 panel.

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

The chemical probe has been well designed and its in vitro and in vivo profile has been thoroughly investigated. The inclusion of a negative control is highly commended, and overall, the probe is fit for use as a selective inhibitor to interrogate the role of the protein.

(last updated: 22 Apr 2022 )

SERP Ratings

In Cell Rating

SERP Comments:

NR162 is a good cellular chemical probe for CASK. The reported binding as well as consistent nanoBRET data with additional characterization in JMC provides a full, but not a complete data set. In particular the TYRO3 off-target could have been explored in more detail. The data suggests only moderate selectivity & in a cellular context some ambiguity remains with nanoBRET not being an endogenous measurement. It would have been good to see data on e.g. downstream phosphorylation makers in relevant cell lines to better understand the true cellular selectivity of NR162; until such data is available it would seem prudent to interpret any cellular activity > 3 uM with caution. The negative control, while similar in structure, will abrogate binding to both kinases. Overall NR162 comes with a nice package and provides the currently best available chemical probe for CASK.

(last updated: 30 Apr 2022 )

SERP+ Ratings

In Cell Rating

SERP+ Comments:

NR162 shows good potency for its target kinase CASK with good kinome-wide selectivity. It shows 48-fold selectivity over its closest off-target TYRO3. To avoid potential phenotypic effects by inhibiting this off-target with an IC50 value of 3.8 µM (as established using a nanoBRET assay), a maximum probe concentration in cellular assays of 1 µM is recommended.

(last updated: 22 Mar 2023 )