JRD-SIK1/2i-4

JRD-SIK1/2i-4 : Inhibitor of SIK1, SIK2

Structure

SERP Rating

In Cells

(1 ratings)

In Model Organisms

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Probe JRD-SIK1/2i-4 is in the process of SERP review.

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Information

SIK1
SIK2

Inhibitor

up to 5 uM
Reviewer recommended concentration: 5 -10 µM

Probe Availability:

DC-Chemicals

In Vitro Validations

Uniprot ID: P57059

Target Class: Kinase

Target SubClass: CAMK

Potency: IC50

Potency Value: 143 nM

Potency Assay: ADP-Glo™ Max assay at high ATP

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

Target aliases:

Serine/threonine-protein kinase SIK1, SNF1LK, SIK, ...

DOI Reference: 10.1073/pnas.2307086120

Uniprot ID: P57059

Target Class: Kinase

Target SubClass: CAMK

Potency: Ki

Potency Value: 3.1 nM

Potency Assay: Eurofins Cerep KinaseProfiler assay at Km ATP

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

Target aliases:

Serine/threonine-protein kinase SIK1, SNF1LK, SIK, ...

DOI Reference: 10.1073/pnas.2307086120

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): Selectivity within target family: SIK isoform selectivity was assessed in SIK1, SIK2, and SIK3 ADP-GloTM Max assays in the presence of 3 mM ATP showing JRD-SIK1/2i-4 to be SIK1/2-selective. Ki for SIK3 was 70 nM. Outside target family: The kinase profile was assessed in a radiometric kinase activity panel (Eurofins Scientific, KinaseProfilerTM) with the concentration of ATP at Km for each kinase. Only four non-SIK kinases (1.4%) out of 327 human wild-type kinases screened were inhibited >50% at a 1 μM inhibitor concentration for both compounds. All four off-target kinases (ABL, LCK, RIPK2, and YES) share the same Thr gatekeeper residue as the SIKs. JRD-SIK1/2i-4 was 82-fold selectivity versus YES and 50-fold selectivity versus RIPK2. The selectivity ratios for the remaining off-target kinases LCK and ABL were ≥100-fold.

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Direct mechanistic SIK1/SIK2 inhibition in cells was analysed by phosphorylation of CRTC3 (Supplemental Figure S2 in DOI 10.1073/pnas.2307086120. There were insufficient data points to calculate an IC50 but it could be around 0.5-1.0 micromolar. Based on that data an appropriate concentration to use may be 5-10 micromolar. The IC50/EC50 values for other cellular assays vary by more than 10x, so the compound may not be acting through the same target(s) in all cases. A cellular IC50/EC50 value for direct SIK1/SIK2 inhibition is needed to accurately determine the suitable compound concentration to use.

(last updated: 26 Mar 2024 )