AZ6102

TNKS2:5 nM|TNKS1:5 nM

Nude mice are administered 25 mg/kg of AZ-6102. The compound has a half-life of 4 hours and a CL of 24 mL/min.kg. Further analysis in mouse and rats shows that AZ-6102 has a moderate bioavailability at 12% and 18%, respectively. Western blot analysis for TNKS1, TNSK2 and Axin2 of treated DLD-1 cells shows that AZ-6102 had qualitatively stronger and longer lasting stabilization of TNSK1, TNSK2 and Axin2 than XAV-939 at lower concentrations (at 24, 48 and 72h). AZ-6102 has good pharmacokinetics in preclinical species with low Caco2 efflux (to avoid possible tumor resistance mechanisms). In addition, the compound can be formulated in a clinically relevant intravenous solution at 20 mg/mL using SBECD as an excipient at pH4. The results of AZ-6102 used as an i.v. probe compound to explore the in vivo effects of the inhibition of TNKS1 and TNSK2 on tumor xenografts and normal tissue are forthcoming[2].

AZ6102 inhibits TNKS1 and TNKS2 in enzymatic assays and TCF4 reporter assays (<5 nM). AZ6102 inhibits proliferation of Colo320DM (GI50 ~40 nM), 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[1].

DMSO:21.4 mg/mL (50 mM)