NMS-P118

Protein target name:

PARP1

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

100 nM - 1 uM

Probe Availability

MedChemExpress

Probe Information

Target and Probe Information

Target Details

Target class:

poly(ADP-ribose) polymerase 1, ADPRT, ADPRT 1, ADPRT1, ARTD1, PARP, PARP-1, PPOL, pADPRT-1

Probe Details

Chemical Probes Portal ID:

CPP1610

Probe alias:

D7N, EX-A1271 CS-6144 HY-18954

PubChem CID:

49843531

ChEMBL ID:

CHEMBL3606021

SMILES string:

C1CC(CCC1N2CCC(CC2)N3CC4=C(C3=O)C(=CC(=C4)F)C(=O)N)(F)F

InChi Key:

ARYVAQSYRLZVQD-UHFFFAOYSA-N

Orthogonal probe:

OlaparibTalazoparibVeliparib

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

0.009 uM

Potency assay:

SPR binding assay

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

5A00

Structure-activity relationship:

Yes, see J Med Chem paper

Off target activity

Potency (off target):

Off target protein and potency:

PARP2: 1.39 uMPARP3 (ARTD3): 0.69 uMTNKS1 (PARP5a): >10 uM

Potency assay (off target):

SPR binding assay

Probe Selectivity in Vitro:

In CYP inhibition assays, NMS-P118 had only moderate activity against two of eight CYP proteins (IC50: CYP2B6 8.15 uM; CYP2D6 9.51 uM). In a panel of 56 kinases, NMS-P118 yielded IC50s > 10 uM.

In cell validation

On target activity in cells

Potency in cells:

IC50

0.04 uM

Potency assay (cells):

In HeLa cells, hydrogen peroxide-induced PAR production was quantified.

Target engagement assay (cells):

Indirect, PAR assay.

Off target activity in cells

Potency in cells, off target:

IC50

Off target protein and potency (cells):

SIRT1: >10 uM

Potency assay, off target (cells):

HeLa cell PAR assay. Also in cells, NMS-P118 potently inhibited proliferation of BRCA1-mutant MDA-MB-436 triple negative breast cancer cells (IC50=0.4 uM) but not non-BRCA1-mutant cell lines (IC50 >10 uM).

In vivo validation

Organism:

Harlan nu/nu mouse, Sprague Dawley rat

Dose:

10 mg/kg

Route of delivery:

OralIntravenous

Plasma half life:

3.3 h (mouse, IV), 3.1 h (mouse, oral)4.7 h (rat, IV), 3.9 h (rat, oral)

Systemic clearance:

19.3 mL/min/kg (mouse, IV); 10.8 (rat, IV)

Cmax:

5.6 uM (mouse, IV), 5.2 uM (mouse, oral)6.0 uM (rat, IV), 2.8 uM (rat, oral)

Organ of Interest

Organ (O):

xenograft

Target engagement assay:

In Caplan-1 xenograft, NMS-P118 inhibited PAR production in the tumor.

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.5b00680

Reference (PMID):

26222319

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

While NMS-P118 is 150-fold selective for PARP-1 over PARP-2 in vitro, cellular target selectivity is not yet clear. However, pharmacokinetics, bioavailability and tolerability in animals are good, so this could be a good in vivo probe.

Jul 28 2017 - 12:33pm

NMS-P118 is a cellularly active and bioavailable selective PARP-1 inhibitor. This chemical probe is an excellent choice for investigating PARP-1 biology either in a cellular or an in vivo context.

Nov 16 2020 - 8:36pm

NMS-P118

Probe Availability

Probe Information

Target Details

poly(ADP-ribose) polymerase 1, ADPRT, ADPRT 1, ADPRT1, ARTD1, PARP, PARP-1, PPOL, pADPRT-1

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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NMS-P118

Probe Availability

Probe Information

Target Details

poly(ADP-ribose) polymerase 1, ADPRT, ADPRT 1, ADPRT1, ARTD1, PARP, PARP-1, PPOL, pADPRT-1

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?