Talazoparib

Reagent Authentication Certificate:

Chemical Probes Portal Talazoparib.pdf

Protein target name:

PARPs

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

10-100 nM

Probe Availability

Cayman (1207456-01-6)

MedChem Express (1207456-01-6)

Probe Information

Target and Probe Information

Target Details

Target class:

ADPRT, ADPRT 1, ADPRT1, ARTD1, PARP, PARP-1, PPOL, pADPRT-1, ADPRT2, ADPRTL2, ADPRTL3, ARTD2, PARP-2, pADPRT-2

Probe Details

Chemical Probes Portal ID:

CPP595

Probe alias:

BMN-673; 1207456-01-6; BMN 673;

PubChem CID:

44819241

ChEMBL ID:

CHEMBL3137320

SMILES string:

CN1C(=NC=N1)[C@@H]2[C@H](N=C3C=C(C=C4C3=C2NNC4=O)F)C5=CC=C(C=C5)F

InChi Key:

IUEWAGVJRJORLA-HZPDHXFCSA-N

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

Ki, IC50

PARP1 1.2 nM, PARP2 0.85 nM (Ki)

Potency assay:

Activity was also assessed in PARP1 enzyme inhibition assay (IC50 = 0.57 nM) and Biacore binding assay with PARP1 (KD = 2.9 X 10^-10 M). In in vitro ribosylation assays, talazoparib had the following activity: IC50 PARP1 (full length)=1.1 nM, PARP2 (full length)=4.1 nM.

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

4UND

Off target activity

Potency (off target):

IC50

Off target protein and potency:

PARP3 62.8 nMPARP4 254 nMTNKS1 322 nMTNKS2 108 nM

Potency assay (off target):

No activity was detected against PARG to 1 uM. In in vitro ADP ribosylation assays, talazoparib was only 15-20-fold selective for PARP1/2 over other PARP proteins (IC50: PARP10=7800 nM, PARP14=25500 nM, PARP15=47400 nM, PAPR16=1900 nM).

Selectivity against non-family targets:

No activity to 10 uM was detected against two panels of off-target proteins: Hit Profile Screening Panel and Adverse Reaction Enzyme Panel (MDS Pharma).

In cell validation

On target activity in cells

Potency in cells:

EC50

2.5 nM

Potency assay (cells):

In LoVe cell PAR synthesis assay

Target engagement assay (cells):

Indirect, PAR synthesis assay

Toxicity

Cytoxicity assay:

Yes

Notes on cytotoxicity:

IC50 = 5 nM in Capan-1 cytotox assay.

In vivo validation

Organism:

Athymic nu/nu mice

Dose:

1 mg/kg

Route of delivery:

Oral

Organ of Interest

Organ (O):

MX-1 tumor xenograft

Target engagement assay:

In MX-1 xenografts, talazoparib inhibited PAR.

Primary Reference

Reference (doi):

10.1158/1078-0432.CCR-13-1391 10.1021/acs.jmedchem.6b00990

Reference (PMID):

44819241 28001384

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

Talazoparib is a PARP 1/2 inhibitor. This agent is an excellent tool to study PARP inhibition in both the cellular and in vivo setting.

Portal staff comment: A new publication appeared in December 2016 (PMID 28001384) indicating that veliparib and niraparib are more selective than talazoparib among PARP family proteins.

Talazoparib is an extremely potent dual PARP1/2 probe, with biochemical potencies against full length PARP1 and PARP2 slightly greater than other clinical PARP inhibitors. It's activity in BRCA1-, BRCA2- and PTEN-deficient cells relative to velaparib, rucaparib and olaparib is particular striking (>50-fold more potent across all cell lines tested). The in vivo efficacy for this compound in MX-1 xenograpft model (BRCA1 deletion) is outstanding, with excellent efficacy seen at 0.33 mg/g dose.

Mechanistic studies with a relatively weak stereoisomer (LT-00674) of talazoparib showed a correlation between biochemical activity and cellular activity, which supports the argument that the surprising activity in vivo is on-target. However, the fact that the compound has significant activity against other PARP family members (pIC50 on PARP3=7.2, TKKS2=6.97) suggests that biological activity related to other PARP family members cannot be ruled out. On the other hand, the compound has been profiled against a set of unrelated protein targets in and against the related protein PARG and was found to be inactive. Therefore, talazoparib can be considered a very useful probe for interrogation in biological experiments, particularly when used in conjunction with other PARP1/2 inhibitors such as velaparib.

Talazoparib

Probe Availability

Probe Information

Target Details

ADPRT, ADPRT 1, ADPRT1, ARTD1, PARP, PARP-1, PPOL, pADPRT-1, ADPRT2, ADPRTL2, ADPRTL3, ARTD2, PARP-2, pADPRT-2

Probe Details

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

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Talazoparib

Probe Availability

Probe Information

Target Details

ADPRT, ADPRT 1, ADPRT1, ARTD1, PARP, PARP-1, PPOL, pADPRT-1, ADPRT2, ADPRTL2, ADPRTL3, ARTD2, PARP-2, pADPRT-2

Probe Details

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?