Background:

IC50: 1 and 3 nM for TNKS2 and TNKS1, respectively

AZ6102 is a TNKS1/2 inhibitor.

Inhibition of the poly(ADP-ribose) polymerase (PARP) catalytic domain of the tankyrases (TNKS1 and TNKS2) is reported to inhibit the Wnt pathway by increasing stabilization of Axin. The canonical Wnt pathway plays a critical role in adult tissue homeostasis, embryonic development, as well as cancer.

In vitro: AZ6102 was identified as a potent TNKS1/2 inhibitor with 100-fold selectivity against other PARP family enzymes including PARPs 1, 2, and 6. In addition, AZ6102 showed a 5 nM IC50 against Wnt pathway in DLD-1 cells [1].

In vivo: In animal study, AZ6102 was intravenously dosed to nude mice at 25 mg/kg, and the results showed that AZ6102 had a clearance of 24 mL/min·kg and a half-life of 4 h. The bioavailability of AZ6102 in mouse and rat was only moderate at 12% and 18%, respectively. In addition, AZ6102 was used as an intravenous probe compound to evaluate the in vivo effects of TNKS1/2 inhibition on normal tissue and tumor xenografts, however, the results of such experiments have not be released so far [1].

Clinical trial: Up to now, AZ6102 is still in the preclinical development stage.

Reference:
[1] J.  W. Johannes, L. Almeida, B. Barlaam,et al.Pyrimidinone nicotinamide mimetics as selective tankyrase and Wnt pathways inhibitors suitable for in vivopharmacology. ACS Med. Chem. Lett. 6, 254-259 (2015).