SCH772984

Reagent Authentication Certificate:

Chemical Probes Portal SCH772984.pdf

Protein target name:

MAPK1, MAPK3

Mechanism of action:

ATP-competitive inhibitor

Recommended Concentration for use in cells:

10 nM - 1 uM

Probe Availability

MedChem Express (942183-80-4)

Cayman (942183-80-4)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

CMGC

HUGO ID:

HGNC:6871 HGNC:6877

Entrez gene ID:

5594 5595

UNIPROT ID:

P28482 P27361

Target alias:

ERK, ERK-2, ERK2, ERT1, MAPK2, P42MAPK, PRKM1, PRKM2, p38, p40, p41, p41mapk, p42-MAPK and ERK-1, ERK1, ERT2, HS44KDAP, HUMKER1A, P44ERK1, P44MAPK, PRKM3, p44-ERK1, p44-MAPK

Probe Details

Chemical Probes Portal ID:

CPP143

PubChem CID:

24866313

ChEMBL ID:

CHEMBL3590107

SMILES string:

C1CN(C[C@@H]1C(=O)NC2=CC3=C(C=C2)NN=C3C4=CC=NC=C4)CC(=O)N5CCN(CC5)C6=CC=C(C=C6)C7=NC=CC=N7

InChi Key:

HDAJDNHIBCDLQF-RUZDIDTESA-N

PAINs evaluation:

PAINs free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

0.24 nM

Potency assay:

Temperature-dependent fluorescence binding assay

Off target activity

Potency assay (off target):

Only 6 off-target kinases showed >50% inhibition at 1 uM (CLK2, FLT4, GSG2, MAP4K4, MINK1, PRKD1, TTK) out of 300 total assayed.

In cell validation

On target activity in cells

Potency assay (cells):

SCH772984 dose-dependently inhibited substrate phosphorylation in cells.

Primary Reference

Reference (doi):

10.1158/2159-8290.CD-13-0070

Reference (PMID):

23614898

External Resources

Available data:

GDSC2

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

SCH772984 is an extremely selective ERK1/2 inhibitor and effectively suppresses MAPK pathway signaling and cell proliferation in BRAF, MEK, and BRAF/MEK inhibitor-resistant tumor models. In vitro resistance has been observed due to a mutation of glycine to aspartic acid (G186D) in the DFG motif of ERK1. SCH772984 induces an unusual binding pocket which is created by an inactive conformation of the phosphate-binding loop and a shift of the α-C helix.

Jun 16 2016 - 5:32pm

SCH772984 inhibits ERK protein kinase with a nanomolar IC50 in vitro (1 nM for ERK2, and 4 nM for ERK4) while being much less potent against MEK1 (IC50 >10 uM). At 1 uM, this probe also inhibits the following kinases: CLK2 (65%), FLT4 (VEGFR3) 60%, GSG2 (Haspin) 51%, MAP4K4 (HGK) 71%, MAPK1 (ERK2) 100%, MINK1 66%, PRKD1 (PKC mu) 50%, TTK* 62%. In contrast to other reported ERK inhibitors (VTX-11e), this inhibitor also inhibits activating phosphorylation of ERK by MEK kinase at 100 nM, and inhibits phosphorylation of ERK downstream substrate pRSK. Prolonged inhibition of ERK with this inhibitor (36 h; 2 uM) leads to the inhibition of C-RAF phosphorylation (S289; S296; S301) by ERK (Mol. Cell 2005; 17; 215-24). This activates C-RAF leading to the increased phosphorylation of ERK. However, even with the increase in ERK phosphorylation, this inhibitor maintains the inhibition of the downstream ERK substrate, pRSK. Furthermore, the compound was active against cancer cells that were resistant against a combination of B-RAF and MEK inhibitors. SCH772984 successfully inhibited ERK and RSK phosphorylation at 2 uM, while a combination of 10 uM PLX4032 (BRAF-inhibitor) and 1 uM Trametinib (MEK inhibitor) was not able to inhibit ERK and RSK phosphorylation in the same cells.

Jun 29 2016 - 7:57pm

SCH772984 is a potent inhibitor of ERK1 and ERK2, with very high selectivity over other kinases, especially when used at concentrations below 1 micromolar. Strong on-target inhibition of ERK signalling (pRSK) and inhibition of ERK activation (pERK) in cellular assays has been demonstrated from concentrations of 100 nanomolar. The unusual protein kinase conformation induced by SCH772984 is associated with slow binding kinetics in vitro and in cell-based systems (see doi: 10.1038/nchembio.1629). SCH779824 is tolerated for in vivo use by intraperitoneal injection (12.5 - 50 mg/kg, twice daily dosing). Target inhibition in vivo is seen, with strong inhibition of ERK activation (pERK, measured 6 h after last dose) in LOX (BRAF-mutant melanoma) human tumor xenografts treated with SCH779824 (12.5 mg/kg i.p).

Aug 25 2016 - 11:40am

SCH772984

Probe Availability

Probe Information

Target Details

ERK, ERK-2, ERK2, ERT1, MAPK2, P42MAPK, PRKM1, PRKM2, p38, p40, p41, p41mapk, p42-MAPK and ERK-1, ERK1, ERT2, HS44KDAP, HUMKER1A, P44ERK1, P44MAPK, PRKM3, p44-ERK1, p44-MAPK

Probe Details

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

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SCH772984

Probe Availability

Probe Information

Target Details

ERK, ERK-2, ERK2, ERT1, MAPK2, P42MAPK, PRKM1, PRKM2, p38, p40, p41, p41mapk, p42-MAPK and ERK-1, ERK1, ERT2, HS44KDAP, HUMKER1A, P44ERK1, P44MAPK, PRKM3, p44-ERK1, p44-MAPK

Probe Details

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?