GSK2973980A

Inhibitor of DGAT1

Structure

SERP Rating

In Cells

(2 ratings)

In Model Organisms

(2 ratings)

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Probe GSK2973980A is in the process of SERP review.

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Information

DGAT1

Inhibitor

Probe Availability:

In Vitro Validations

Uniprot ID: O75907

Target Class: Other

Target SubClass: Diacylglycerol O-acyltransferase

Potency: IC50

Potency Value: 3.3 (human), 13 (rat) nM

Potency Assay: Radiometric lipid extraction assay (enzymatic assay)

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

Structure-activity relationship: yes

Target aliases:

Diacylglycerol O-acyltransferase 1, DGAT, AGRP1, D ...

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): Radiometric Assay

Probe Selectivity in Vitro:

Within Target Family: exhibited >2900-fold selectivity over human DGAT2, ACAT1 (SOAT1), and ACAT2 (SOAT2) enzymes (IC50 values of >10 μM).

Outside Target Family: excellent cardiac ion channel profile with IC50 values of >10 μM in the hERG, Nav1.5, and Cav1.2 QPatch assays and exhibited good selectivity profile (>700-fold over hDGAT1 LE IC50) across a panel of selectivity assays; minimal CYP inhibition with IC50 values of >10 μM across CYP1A2 (phenacetin), CYP2C9 (diclofenac), CYP2C19 (S-mephenytoin), CYP2D6 (DEX), and CYP3A4 (midazolam), and demonstrated no time-dependent CYP inhibition at up to 50 μM.

Potency assay, off target (cells): Thermal Shift Assay

Probe Selectivity in Cell:

Out of the 7103 quantified proteins, in addition to DGAT1, the thermal stability of only two other proteins, namely epoxide hydrolase (EPHX2) and the epimerase family protein (SDR39U1), was reproducibly altered.

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Regarding the doses used in vivo and mode of delivery, one needs to think about the goal of the experiment. The authors observed high inhibition of triglyceride synthesis in mice at a low dose of 0.088 mg/kg mostly due to DGAT1 inhibition in the GI tract where the compound’s concentration is likely to be significantly higher during drug absorption following oral dosing. Studying compound effect a few hours (4 and 15 selected by the authors) after dosing or using a parenteral route of administration are ways to evaluate systemic DGAT1 inhibition without the effect on enterocytes during compound absorption.

(last updated: 20 May 2021 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

GSK2973980A has an acceptable in-vitro profile against its primary target and the off-targets that have been explored. There remains the possibility of in-vivo effects (desired efficacy and safety/toxicity) are due to poly-pharmacology, therefore it is suggested that additional data is generated. This could include profiling of GSK2973980A against a panel of protein targets from a variety of classes.

(last updated: 5 Aug 2021 )