GPLG3970

GPLG3970 : Inhibitor of SIK2, SIK3

Structure

SERP Rating

In Cells

(1 ratings)

In Model Organisms

(1 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.

Probe GPLG3970 is in the process of SERP review.

Please continue to check back for new reviews and commentary.

Information

SIK2
SIK3

Inhibitor

up to 1 uM

In Vitro Validations

Uniprot ID: Q9H0K1

Target Class: Kinase

Target SubClass: CAMK

Potency: IC50

Potency Value: 7.8 nM

Potency Assay: ADP-Glo Kinase Assay with SIK2

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

Target aliases:

Serine/threonine-protein kinase SIK2, SNF1LK2, QIK ...

DOI Reference: 10.1021/acs.jmedchem.3c02246

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): Selective agains SIK1 IC50 282.8 nM The inhibition of enzymatic activity by GPLG3970 at a concentration of 1 μM was assessed against a panel of 372 kinases. GPLG3970 had a percentage of inhibition (PIN) of kinase activity above 50% on only three other kinases: RIPK2 (79%), ABL1 (58%), and MKNK2 (54%). Further characterization led to IC50 values of 78.4 nM (RIPK2), 1,095 nM (ABL1), and 1,074 nM (MKNK2).

Potency assay, off target (cells): NanoBRET assay SIK1 IC50 >17500 nM

I have extra information to add

SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

GLPG3970 is an advanced molecule which was tested in clinical trials up to Phase 2. As such it is suitable for both cellular and in vivo use to study its main targets SIK2 and SIK3. GLPG3970 displayed cellular target engagement IC50s of 254 nM for SIK2 and 79 nM for SIK3 with selectivity against SIK1 (IC50 > 17,500 nM) in nanoBRET assays in HEK cells. It displayed cytokine secretion IC50s of 67 to 365nM in human monocytes and macrophages. Its maximum recommended concentration for use in cells is 1,000 nM; higher concentrations may bring in additional kinases (e.g. RIPK2,…) and deliver untrustworthy results. No murine cellular potency data was provided in the original publication describing GLPG3970. However, the in vivo TNFa IC50 obtained was 705 nM, which suggests similar potency against murine and human enzymes. Notably, GLPG3970 can be administered orally to mice but twice daily dosing is likely required for consistent target coverage based on the experiments presented. Recommended doses are 10 (mid) and 60 (high) mg/kg p.o. b.i.d.

(last updated: 1 Jul 2024 )