AZ6102
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 & tolerability profile
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.
Mechanism of Action
Tankyrase 1 and 2 (TNKS1/2) inhibitor
Original Therapeutic Area
Oncology
CNS Penetrant
Unknown
Route of administration
IV
Modality
Small Molecule
Additional Information
1. Johannes JW., et al. (2015).
Pyrimidinone Nicotinamide Mimetics as Selective Tankyrase and Wnt Pathway Inhibitors Suitable for in Vivo Pharmacology; ACS Med. Chem. Lett. 2015, 6, 3, 254–259. DOI: 10.1021/ml5003663.