AZ6102

NAD+ competitive inhibitor of TNKS, TNKS2

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(2 ratings)

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Information

TNKS
TNKS2

NAD+ competitive inhibitor

Probe Availability:

In Vitro Validations

Uniprot ID: O95271

Target Class: Other post-translational modification

Target SubClass: PARP

Potency: IC 50

Potency Value: 3 nM

Potency Assay: Scintillation Proximity Assay (SPA): The assay was designed to measure compound inhibition of Tankyrase-1 autoPARsylation (Tankyrase-1 was both enzyme and substrate in this assay).

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

Structure-activity relationship: Yes

Target aliases:

Poly [ADP-ribose] polymerase tankyrase-1, TNKS1, T ...

DOI Reference: 10.1021/acs.jmedchem.6b00990

Uniprot ID: O95271

Target Class: Other post-translational modification

Target SubClass: PARP

Potency: IC 50

Potency Value: 100 nM

Potency Assay: In vitro ADP ribosylation assays

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

Target aliases:

Poly [ADP-ribose] polymerase tankyrase-1, TNKS1, T ...

DOI Reference: 10.1021/acs.jmedchem.6b00990

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 PARP1 2 uM, PARP2 0.5 uM, PARP6 >5 uM

Potency assay (off target): SPA or BPS PARP assay kit. In in vitro ADP ribosylation assays, AZ-6102 was selective for TNKS1/2 over other PARP family members. (IC50: full length PARP1=1600 nM, full length PARP2=990 nM, PARP14=3400 nM, PARP15=25600 nM, with no activity detected against PARP3, PARP4, PARP10).

Probe Selectivity in Vitro:

SPA or BPS PARP assay kit. In in vitro ADP ribosylation assays, AZ-6102 was selective for TNKS1/2 over other PARP family members. (IC50: full length PARP1=1600 nM, full length PARP2=990 nM, PARP14=3400 nM, PARP15=25600 nM, with no activity detected against PARP3, PARP4, PARP10).

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

AZ6102 shows good inhibition of TNK1/2 with selectivity against other related enzymes of the PARP family. Data about other potential off targets (e.g., other NAD+-dependent enzymes or protein kinases) are not shown. AZ6102 has an IC50 in the same low nanomolar range for the isolated enzyme (TNKS1) as well as in the cellular assays. This could be a hint that AZ6102 also interferes with targets other than PARPs in cells. Experiments in a xenograft model with AZ6102 have been announced by the authors, but they are not yet published.

(last updated: 12 Aug 2016 )

SERP Ratings

In Cell Rating

In Model Organisms

(last updated: 20 Jan 2017 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Although two independent papers report that this is a potent (low nM) TNKS2 inhibitor, they report significant discrepancies in TNKS1 inhibition (3 and 100 nM). The oral bioavailability is modest (F = 12% mouse, 18% rat), so it would probably be best to stick to IV formulations.

(last updated: 11 Apr 2017 )