ARS-1620

Protein target name:

KRAS

Mechanism of action:

Atropisomeric Covalent Inhibitor

Recommended Concentration for use in cells:

0.3 - 3.0 uM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

Mutant G12C

HUGO symbol:

HGNC:6407

Entrez gene ID:

3845

Target alias:

NS; NS3; OES; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; C-K-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; K-Ras 2; 'C-K-RAS; c-Ki-ras; c-Ki-ras2

Probe Details

Chemical Probes Portal ID:

CPP1855

PubChem CID:

137003167

ChEMBL ID:

CHEMBL4214264

SMILES string:

C=CC(N1CCN(C2=C3C=C(Cl)[C@@]([C@@]4=C(O)C=CC=C4F)=C(F)C3=NC=N2)CC1)=O.[S]

InChi Key:

ZRPZPNYZFSJUPA-UHFFFAOYSA-N

Control compound:

R-atropisomer

Orthogonal probe:

AMG-510MRTX849

Physico-chemical properties

NMR:

1H NMR (400 MHz, DMSO-d6): δ 10.28 (brs, 1H), 8.69 (s, 1H), 8.04 (s, 1H), 7.39-7.33 (m, 1H), 6.86-6.78 (m, 3H), 6.18 (dd, J = 2.6, 16.7 Hz, 1H), 5.75 (dd, J = 1.8, 10.1 Hz, 1H), 3.92-3.76 (m, 8 H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

kobs/[I]

1,100 ± 200 M−1s−1

Potency assay:

Biochemical Binding Assay

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

5V9U

Structure-activity relationship:

yes

In cell validation

On target activity in cells

Potency in cells:

IC50

120 nM

Potency assay (cells):

Inhibition of RAS signalling

Target engagement assay (cells):

LC/MS-MS analysis of KRASG12C engagement (G12C-TE) following treatment of H358 cells with ARS-1620

Off target activity in cells

Selectivity against nonfamily targets (cells):

Proteome and Transcriptome Profiling the Functional Selectivity of ARS-1620 for KRASG12C and Associated Gene Transcription Signatures

In vivo validation

Organism:

Mouse

Dose:

50 mg/Kg200 mg/Kg

Route of delivery:

Oral

Plasma half life:

2.5 h (Mouse)3.5 h (Human)

Fraction of probe bound to plasma protein:

65%

Primary Reference

Reference (doi):

10.1016/j.cell.2018.01.006 10.1158/1078-0432.CCR-19-3523 10.1038/s41467-020-16309-2

Reference (PMID):

29373830 31776128 32499547

ARS-1620

Probe Availability

Probe Information

Target Details

NS; NS3; OES; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; C-K-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; K-Ras 2; 'C-K-RAS; c-Ki-ras; c-Ki-ras2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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ARS-1620

Probe Availability

Probe Information

Target Details

NS; NS3; OES; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; C-K-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; K-Ras 2; 'C-K-RAS; c-Ki-ras; c-Ki-ras2

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?