AZ6102

Reagent Authentication Certificate:

Chemical Probes Portal AZ6102.pdf

Protein target name:

TNKS, TNKS2

Mechanism of action:

NAD+ competitive inhibitor

Recommended Concentration for use in cells:

50-500 nM

Probe Availability

MedChem Express (1645286-75-4)

Tocris (1645286-75-4)

Cayman (1645286-75-4)

Probe Information

Target and Probe Information

Target Details

Target class:

TIN1, ARTD5, PARPL, TINF1, TNKS1, pART5, PARP5A, PARP-5a, TNKL, ARTD6, TANK2, pART6, PARP5B, PARP5C, PARP-5b, PARP-5c

Probe Details

Chemical Probes Portal ID:

CPP588

Probe alias:

CS-510

PubChem CID:

91663328

SMILES string:

C[C@@H]1CN(C[C@@H](N1)C)C2=NC=C(C(=C2)C)C3=CC=C(C=C3)C4=NC(=O)C5=C(N4)N(C=C5)C

InChi Key:

WCPTUQOMNJBIET-CALCHBBNSA-N

Orthogonal probe:

XAV939JW55

Physico-chemical properties

Solubility - preferred solvent:

DMSO

Solubility - concentration:

10 mM

NMR:

1 H NMR (500 MHz, DMSO, 30 °C) δ ppm 1.04 (6H, d), 2.26 (5H, m), 2.76 (2H, ddd), 3.79 (3H, s), 4.19 (2H, dd), 6.48 (1H, d), 6.78 (1H, s), 7.12 (1H, d), 7.48 (2H, d), 7.98 (1H, s), 8.23 (2H, d), 12.01 (1H, m)

Storage Recommendations

Storage (dry powder):

4 °C

Storage (solution):

4 °C

Storage sensitivities:

Slightly sensitive to strong acid, avoid prolonged exposure to air.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

TNKS 0.003 uM, TNKS2 0.001 uM

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). In in vitro ADP ribosylation assays, AZ-6102 showed the following activity: IC50- TNKS1=100 nM, TNKS2=0.6 nM.

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

4W5S, 4W6E

Structure-activity relationship:

Yes,

Off target activity

Potency (off target):

IC50

Off target protein and potency:

PARP1 2 uMPARP2 0.5 uMPARP6 >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:

Not available

In cell validation

On target activity in cells

Potency in cells:

IC50

0.005 uM

Potency assay (cells):

Inhibition of the Wnt pathway as demonstrated in a TCF TOPflash reporter assay in DLD-1 cells.

Target engagement assay (cells):

Indirect, AZ6102 stabilizes Axin in DLD-1 cells.

In vivo validation

Organism:

Rat, Nude mouse

Dose:

25 mg/kg IV (mouse)

Route of delivery:

OralIntravenous

Plasma half life:

5.7 hr (rat IV)4.3 hr (mouse IV)

Systemic clearance:

11 mL/min•kg (rat IV), 24 mL/min•kg (mouse IV)

Fraction of probe bound to plasma protein:

0.88 (mouse oral)0.82 (rat oral)

Primary Reference

Reference (doi):

10.1021/ml5003663 10.1021/acs.jmedchem.6b00990

Reference (PMID):

25815142 28001384

External Resources

Available data:

GDSC2

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB 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.

Aug 12 2016 - 5:48pm

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.

Apr 12 2017 - 12:53pm

AZ6102

Probe Availability

Probe Information

Target Details

TIN1, ARTD5, PARPL, TINF1, TNKS1, pART5, PARP5A, PARP-5a, TNKL, ARTD6, TANK2, pART6, PARP5B, PARP5C, PARP-5b, PARP-5c

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

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AZ6102

Probe Availability

Probe Information

Target Details

TIN1, ARTD5, PARPL, TINF1, TNKS1, pART5, PARP5A, PARP-5a, TNKL, ARTD6, TANK2, pART6, PARP5B, PARP5C, PARP-5b, PARP-5c

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?