PDD00017273

PDD00017273 : PolyADP ribose (PAR) competitive inhibitor of PARG

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(1 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

PARG

PolyADP ribose (PAR) competitive inhibitor

Up to 10 uM, or 10X the cellular IC50 depending on the cell line

DOI - 10.1021/acschembio.6b00609

Probe Availability:

In Vitro Validations

Uniprot ID: Q86W56

Target Class: DNA replication & repair enzyme

Target SubClass: Glycohydrolase

Potency: IC50

Potency Value: 26 nM

Potency Assay: Biochemical PAR chain persistence assay

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

Target aliases:

Poly(ADP-ribose) glycohydrolase, PARG, PARG_HUMAN

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency assay (off target): Biochemical PAR chain persistence assay

Probe Selectivity in Vitro:

Biochemical selectivity against safety targets (% inhibition at 10 µM, binding assay Eurofins Panlabs): Adenosine A1=1%, Adenosine A2A=-1%, Adrenergic a1A=-5%, Adrenergic a1B=7%, Adrenergic a2A=10%, Adrenergic β1=-9%, Adrenergic β2=-9%, Calcium Channel=L Type=16%, Cannabinoid CB1=21%, Dopamine D1=6%, Dopamine D2S=-9%, GABAA=Flunitrazepam Central=4%, GABAA=Muscimol Central=3%, Glutamate=NMDA=4%, Histamine H1=-6%, Imidazoline I2=Central=-18%, Muscarinic M2 =-1%, Muscarinic M3 =3%, Nicotinic Acetylcholine=3%, Nicotinic Acetylcholine=a1=-3%, Opiate µ(OP3=MOP)=-6%, Phorbol Ester=-11%, Potassium Channel [KATP]=5%, Potassium Channel hERG=12%, Prostanoid EP4=11%, Rolipram=16%, Serotonin (5-Hydroxytryptamine) 5-HT2B=4%, Sigma σ1=15%, Sodium Channel site 2=6%, Transporter=Norepinephrine (NET)=20%, Acetyl Cholinesterase=-1%, Cyclooxegenase COX-2=-2%, Phosphodiesterase PDE4=17%

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

(last updated: 11 Jan 2017 )

SERP Ratings

In Cell Rating

SERP Comments:

PD00017273 is an inhibitor of human PARG enzyme with IC50 of 26 nM and good selectivity over the two closest functional homologues, PARP1 and ARH3 (>100 μM). It is suitable for use in cellular assays (cell permeability data not available) and is not cytotoxic in HeLa cells up to 30 μM; however, different sensitivities in different cell lines are possible. Interestingly, the negative control (compound 6) also shows some weak activity in the Promega Glo assay. Off-target activity is not completely ruled out, since the compound was tested on a relatively small panel of 33 receptors and enzymes at 10 μM. PD00017273 is far a better compound compared with the previously reported PARG inhibitor, and it can used as chemical tool to investigate PARG biology. Due to high intrinsic clearance in HLM, the compound is not suitable for use for any in vivo studies.

(last updated: 27 Jan 2017 )

SERP Ratings

In Cell Rating

SERP Comments:

PDD00017273 is a potent inhibitor of PARG in cells (EC₅₀=37 nM in a cellular PAR chain persistence assay) with little toxicity observed at 10 µM. While some degree of selectivity screening has been performed—for example, PDD00017273 is inactive at the related protein ARH3 and also at PARP1—a larger body of characterization data would be preferred for the informed deconvolution of cellular usage of the compound. The availability of a negative control compound inactive at the primary target increases the utlity of the compound. PDD00017273 shows poor metabolic stability in human liver microsomes and is thus unlikely to be useful as an in vivo probe.

(last updated: 18 Apr 2017 )