JA310

JA310 : Inhibitor of STK24

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

STK24

Inhibitor

up to 1 uM

Additional Data

SGC Chemical Probe Collection

In Vitro Validations

Uniprot ID: Q9Y6E0

Target Class: Kinase

Target SubClass: STE

Potency: ΔTm

Potency Value: 7.5 ± 0.6 Kelvin

Potency Assay: DSF

PDB ID for probe-target interaction (3D structure): 8QLQ

Target aliases:

Serine/threonine-protein kinase 24, STK3, MST3, ST ...

DOI Reference: 10.1021/acs.jmedchem.3c01980

Uniprot ID: Q9Y6E0

Target Class: Kinase

Target SubClass: STE

Potency: IC50

Potency Value: 76 nM

Potency Assay: NanoBRET in lysed HEK293 cells

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

Target aliases:

Serine/threonine-protein kinase 24, STK3, MST3, ST ...

DOI Reference: 10.1021/acs.jmedchem.3c01980

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency assay (off target): DSF confirmed stabilization of MST3 and MST4 but not MST2 and MST3. Outside the MST family, JA310 stabilized five other kinases (CLK1, GSK3B, MELK, RIOK1, and STK6) in a range of 5.1–6.5 °C. JA310 was tested against 340 wild-type kinases at a screening concentration of 1 μM, revealing excellent selectivity with a selectivity score (S40) of 0.012.

Potency assay, off target (cells): In NanoBRET, JA310 showed comparatively weaker activity for MST4, with EC50 values of 1.4 μM and 362 nM for the intact and permeabilized cells, respectively. The two related family members MST1 and MST2 were not affected (EC50 values > 50 μM). NanoBRET assays were performed in intact and in permeabilized cells to determine the EC50 values for all off-targets with the percent of control values below 40%. The next identified off-target outside the MST family was LIMK2, which was inhibited with EC50 values of 1.4 and 1.8 μM in intact and permeabilized cells, respectively.

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

Macrocyclic compound JA310 demonstrates exquisite selectivity across the kinome. Selectivity against closely related isoform MST4 is 4-5fold in permeabilized cells. What is not immediately clear, is the differences in selectivity for MST3 vs MST4 in intact vs permeabilized cells in NanoBret assay. Biochemical activity is confirmed in orthogonal assays and crystallographic data further confirms target engagement and mode of action as an ATP competitive kinase inhibitor.

(last updated: 24 Mar 2024 )

SERP+ Ratings

In Cell Rating

SERP+ Comments:

The chemical probe achieved remarkable selectivity whithin the kinome (340 wild-type kinases) due to its macrocyclic nature. Moreover, it is an ATP-competitive inhibitor that also induces conformational changes in the active site, making it a particularly interesting probe. The compound has a high cellular potency for MST3. In Vitro potency was evaluated and found to be less than 100 nM (76 nM) and EC50 = 106 nM for MST3. Selectivity was around 10-fold for closest off target. Lack of toxicity at concentration under 10 uM. A negative control is available (JA262).

(last updated: 23 May 2024 )

SERP+ Ratings

In Cell Rating

SERP+ Comments:

This is a highly potent probe with high selectivity over 340 kinases. No toxicity at concentrations lower than 2 µM has been observed. The compounds seemd to possess sufficient solubility for typical in vitro assays. An alternative MST3/4 probe has been published here: DOI: 10.1021/acs.jmedchem.3c02217

(last updated: 17 Jun 2024 )