GSK2982772

Protein target name:

RIPK1

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 300 nM

Probe Availability

MedChemExpress

Selleck Chemicals

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

TKL

HUGO ID:

HGNC:10019

Entrez gene ID:

8737

UNIPROT ID:

Q13546

Target alias:

RIP; RIP1; AIEFL; IMD57; RIP-1

Probe Details

Chemical Probes Portal ID:

CPP2056

Probe alias:

7MJ, Cpd 5

PubChem CID:

77108121

ChEMBL ID:

CHEMBL4071864

SMILES string:

O=C(C1=NC(CC2=CC=CC=C2)=NN1)N[C@H]3COC4=CC=CC=C4N(C)C3=O

InChi Key:

LYPAFUINURXJSG-AWEZNQCLSA-N

Orthogonal probe:

GSK481

Physico-chemical properties

Solubility - concentration:

443 uM

Potential reactivities:

not known

NMR:

1H NMR (DMSO-d6) δ ppm 14.41 (br s, 1 H), 8.48 (br s, 1 H), 7.50 (dd, J = 7.7, 1.9 Hz, 1 H), 7.12–7.40 (m, 8 H), 4.83 (dt, J = 11.6, 7.9 Hz, 1 H), 4.60 (t, J = 10.7 Hz, 1 H), 4.41 (dd, J = 9.9, 7.8 Hz, 1 H), 4.12 (s, 2 H), 3.31 (s, 3 H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

16 nM (FP), 1 nM (ADP-Glo)

Potency assay:

FP binding assay and ADP-Glo Assay

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

5TX5

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

GSK2982772 shows more than 1,000-fold selectivity for ERK5 over a panel of over 339 kinases Reaction Biology and on competition binding assay KINOMEscan at DiscoveRx Corp (456 kinases) both at 10 μM.

In cell validation

On target activity in cells

Potency in cells:

IC50

0.5 nM, 2 nM (W.B. assay)

Potency assay (cells):

RIP1-dependent inflammatory cytokine MIP-1β production. Human whole blood stimulation assay; coincubation of TNF with both the caspase inhibitor QVD-OPh and the SMAC mimetic RMT 5265, which block the apoptosis and NF-κB pathways, respectively, driving the TNF response down the necroptosis pathway; IL-1β and IL-6 production in ulcerative colitis explant tissue

Off target activity in cells

Probe Selectivity in Cell:

GSK2982772 demonstrated a clean profile against a range of nonkinase targets. No inhibitory potential toward recombinant human cytochrome P450 (CYP) enzymes, with the exception of weak activity against CYP2C9 (IC50 = 25 μM). Weak concentration-dependent inhibition of hERG in human embryonic kidney (HEK-293) cells, with an estimated IC50 of 195 μM, and showed a weak activation of the human Pregnane X receptor (hPXR) with an EC50 of 13 μM.

In vivo validation

Organism:

RatMonkey

Dose:

1.1 (R) - 1.2 (M) mg/Kg2.1 (R) - 1.9 (M) mg/KgReviewer suggested 5-50 mg/Kg PO

Route of delivery:

OralIntravenous

Plasma half life:

3.9 ± 0.7 (R), 6.5 ± 1.0 (M) h (IV)

Systemic clearance:

17 ± 5 (R), 10 ± 3(M) ml/min/Kg (IV)

Cmax:

810 ± 160 (R) 720 ± 240 (M) ug/ml (PO)

Tmax:

0.25 ± 0.0 (R), 1.8 ± 1.1(M) h (PO)

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.6b01751

Reference (PMID):

28151659

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

The probe should be used in cellular system in combination with its enantiomer as negative control. Importantly, this probe shows significant species-differences as outlined by the authors in the J. Med. Chem. paper. Therefore, the probe can only be used in rodent acute models at relatively high doses (5-50 mg/Kg po, total systemic concentration significantly exceeding the recommended concentration range for cellular studies). When using the probe at these doses observed phenotypes will have to be linked back to on target activity by providing PK-PD correlations for proximal PD markers or the used of ko animals as controls.

Dec 2 2020 - 10:12am

The enantiomer is very useful as a negative control probe. For orthogonal probe, e.g. in Cortellis Drug Discovery Intelligence there are 286 small molecules with Mw <750 g/mol that are used in either biological testing or preclinical phase as RIPK1 inhibitors.

Dec 14 2020 - 8:36am

GSK2982772

Probe Availability

Probe Information

Target Details

RIP; RIP1; AIEFL; IMD57; RIP-1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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GSK2982772

Probe Availability

Probe Information

Target Details

RIP; RIP1; AIEFL; IMD57; RIP-1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?