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Talazoparib

Inhibitor of PARP1, PARP2

Structure

Information

  • PARP1
  • PARP2
  • Inhibitor
  • 10-100 nM

In Vitro Validations

Uniprot ID: P09874
Target Class: Other post-translational modification
Target SubClass: PARP
Potency: IC 50
Potency Value: 1.2 nM
Potency Assay: Biochemical assay
PDB ID for probe-target interaction (3D structure): 4UND
Target aliases:
Poly [ADP-ribose] polymerase 1, PPOL, ADPRT, PARP1 ...

DOI Reference: 10.1021/acs.jmedchem.6b00990

Uniprot ID: P09874
Target Class: Other post-translational modification
Target SubClass: PARP
Potency: IC 50
Potency Value: 0.57 nM
Potency Assay: PARP1 enzyme inhibition assay
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Poly [ADP-ribose] polymerase 1, PPOL, ADPRT, PARP1 ...

DOI Reference: 10.1021/acs.jmedchem.6b00990

Uniprot ID: P09874
Target Class: Other post-translational modification
Target SubClass: PARP
Potency: Kd
Potency Value: 0.29 nM
Potency Assay: Biacore binding assay with PARP1
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Poly [ADP-ribose] polymerase 1, PPOL, ADPRT, PARP1 ...

DOI Reference: 10.1021/acs.jmedchem.6b00990

Uniprot ID: P09874
Target Class: Other post-translational modification
Target SubClass: PARP
Potency: IC 50
Potency Value: 1.1 nM
Potency Assay: In vitro ribosylation assays, PARP1 (full length)
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Poly [ADP-ribose] polymerase 1, PPOL, ADPRT, PARP1 ...

DOI Reference: 10.1021/acs.jmedchem.6b00990

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 PARP3 62.8 nM, PARP4 254 nM, TNKS1 322 nM, TNKS2 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).
Probe Selectivity in Vitro:
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). 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).
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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

SERP 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. 

(last updated: 13 Apr 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

(last updated: 4 May 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

(last updated: 15 Jun 2017 )