GSK2973980A

Protein target name:

DGAT1

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 100 uM

Probe Availability

MedKoo Biosciences, Inc.

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

Metabolic Enzyme

Subclass:

Diacylglycerol O-acyltransferase

HUGO ID:

HGNC:2843

Entrez gene ID:

8694

UNIPROT ID:

O75907

Target alias:

ARAT; DGAT; ARGP1; DIAR7

Probe Details

Chemical Probes Portal ID:

CPP2062

Probe alias:

26d

PubChem CID:

137628648

ChEMBL ID:

CHEMBL4173715

SMILES string:

O=C(O)C[C@@](CCC1=C2C=CC(C3=NC=C(NC(NC4=CC=C(F)C(F)=C4)=O)N=C3)=C1)(CC(F)(F)F)C2=O

InChi Key:

OTKTZEZTFCAULO-DEOSSOPVSA-N

Orthogonal probe:

AZD3988

PAINs evaluation:

PAINS-Free

Physico-chemical properties

Solubility - concentration:

134 ug/mL

NMR:

1H NMR (300 MHz, DMSO-d6): δ 12.42 (bs, 1H), 9.83 (s, 1H), 9.77 (s, 1H), 9.16 (d, J = 1.2 Hz, 1H), 9.02 (d, J = 1.5 Hz, 1H), 8.1-7.94 (m, 3H), 7.78-7.68 (m, 1H), 7.46-7.35 (m, 1H), 7.24 (m, 1H), 3.41-3.35 (m, 1H), 3.20-2.95 (m, 2H), 2.88-2.80 (m, 2H), 2.65-2.55 (m, 1H), 2.50-2.42 (m, 1H), 2.24- 2.14 (m, 1H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

3.3 (human), 13 (rat) nM

Potency assay:

Radiometric lipid extraction assay (enzymatic assay)

Structure-activity relationship:

yes

Off target activity

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.

In cell validation

On target activity in cells

Potency in cells:

IC50

75 nM

Potency assay (cells):

Inhibition of TG synthesis.

Target engagement assay (cells):

Evidence of target engagement in HepG2 cells was demonstrated using a cellular thermal shift assay combined with multiplexed quantitative mass spectrometry.

Off target activity in cells

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.

In vivo validation

Organism:

Mouse (C57BL/6J, male)Rat (Sprague-Dawley, male)Dog (Beagle, male)

Dose:

1, 3, 10 mg/Kg

Route of delivery:

OralIntravenous

Plasma half life:

2.6 h

Systemic clearance:

3.3 (R), 13.3 (M), 5.1 (D) mL/min/kg

Fraction of probe bound to plasma protein:

48%

Primary Reference

Reference (doi):

10.1021/acsmedchemlett.7b00450 10.9734/JPRI/2017/36835

Reference (PMID):

29456796

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB 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.

May 20 2021 - 1:11pm

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.

Aug 5 2021 - 9:03am

GSK2973980A

Probe Availability

Probe Information

Target Details

ARAT; DGAT; ARGP1; DIAR7

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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GSK2973980A

Probe Availability

Probe Information

Target Details

ARAT; DGAT; ARGP1; DIAR7

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?