Mechanism of action: Tankyrase 1 and 2 inhibitor (TNKS1/2) inhibitor

Preclinical pharmacology

AZ6102 inhibits TNKS1 and TNKS2 in enzymatic assays and TCF4 reporter assays (<5nM).

AZ6102 inhibits proliferation of Colo320DM (GI50 ~40nM), but has no anti-proliferative activity in the β-catenin mutant cell line HCT-116, or the BRCA mutant cell line MDA-MB-436. In Colo320DM, AZ6102 stabilizes axin2 protein and modulates Wnt target genes in a dose and time dependent manner both in vitro and in vivo.

Safety and tolerability

Tankyrases are important for normal gastrointestinal physiology. As such continuous complete inhibition of tankyrase activity is expected to result in on-target GI toxicity.

Tolerated doses and schedules for AZ6102 in mice have been identified and include up to 15mg/kg iv daily and 120mg/kg iv twice a week.

Additional information

Publications for this compound

Find out more about this compound by reading related publications:

ACS Medicinal Chemistry Letters

Pyrimidinone Nicotinamide Mimetics as Selective Tankyrase and Wnt Pathway Inhibitors Suitable for in Vivo Pharmacology

Gene information from the NCBi

This compound works on the following genes: