AZ6102 is a potent and dual inhibitor of tankyrases TNKS1/2 with IC50 values of 3 nM and 1 nM, respectively, it has 100-fold selectivity against other PARP family enzymes and shows 5 nM Wnt pathway inhibition in DLD-1 cells. AZ6102 exhibits good pharmacokinetics in preclinical species, is well-formulated at a clinically relevant intravenous solution concentration of 20 mg/mL, and has low Caco2 efflux to prevent potential tumor resistance mechanisms. The development of embryos, adult tissue homeostasis, and cancer are all significantly impacted by the canonical Wnt pathway. Oncogenesis can result from germline mutations in ß-catenin, Axin, and APC, three elements of the Wnt pathway. Through increased stabilization of Axin, inhibition of the poly(ADP-ribose) polymerase (PARP) catalytic domain of tankyrases (TNKS1 and TNKS2) is known to inhibit the Wnt pathway.
Physicochemical Properties
| Molecular Formula | C25H28N6O |
| Molecular Weight | 428.54 |
| Exact Mass | 428.232 |
| Elemental Analysis | C, 70.07; H, 6.59; N, 19.61; O, 3.73 |
| CAS # | 1645286-75-4 |
| Related CAS # | 1645286-75-4 |
| PubChem CID | 135905416 |
| Appearance | Light yellow to yellow solid powder |
| Density | 1.3±0.1 g/cm3 |
| Index of Refraction | 1.694 |
| LogP | 2.81 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 32 |
| Complexity | 709 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | O=C1C2C([H])=C([H])N(C([H])([H])[H])C=2N=C(C2C([H])=C([H])C(=C([H])C=2[H])C2=C([H])N=C(C([H])=C2C([H])([H])[H])N2C([H])([H])[C@@]([H])(C([H])([H])[H])N([H])[C@@]([H])(C([H])([H])[H])C2([H])[H])N1[H] |
| InChi Key | WCPTUQOMNJBIET-CALCHBBNSA-N |
| InChi Code | InChI=1S/C25H28N6O/c1-15-11-22(31-13-16(2)27-17(3)14-31)26-12-21(15)18-5-7-19(8-6-18)23-28-24-20(25(32)29-23)9-10-30(24)4/h5-12,16-17,27H,13-14H2,1-4H3,(H,28,29,32)/t16-,17+ |
| Chemical Name | 2-[4-[6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-4-methylpyridin-3-yl]phenyl]-7-methyl-3H-pyrrolo[2,3-d]pyrimidin-4-one |
| Synonyms | AZ6102; AZ-6102; AZ 6102 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | TNKS2 ( IC50 = 2 nM ); TNKS1 ( EC50 = 3 nM ); TNKS1 ( EC50 = 2 μM ); TNKS1 ( EC50 = 0.5 μM ) |
| ln Vitro | AZ6102 inhibits TNKS1 and TNKS2 in enzymatic assays and TCF4 reporter assays (<5nM). AZ6102 has no anti-proliferative effect on the β-catenin mutant cell line HCT-116 or the BRCA mutant cell line MDA-MB-436, but it does inhibit the growth of Colo320DM (GI50 ~40nM). In vitro and in vivo, AZ6102 stabilizes axin2 protein and modifies Wnt target genes in Colo320DM in a dose- and time-dependent manner[1]. |
| ln Vivo | AZ-6102 (25 mg/kg) is given to naked mice. Its CL is 24 mL/min.kg and its half-life is 4 hours. Upon additional examination in mice and rats, AZ-6102 demonstrates a moderate bioavailability of 12% and 18%, respectively. Analysis of treated DLD-1 cells using Western blot for TNKS1, TNSK2, and Axin2 reveals that, at lower concentrations (at 24, 48, and 72 hours), AZ-6102 stabilized TNSK1, TNSK2, and Axin2 qualitatively stronger and longer than XAV-939. To prevent potential tumor resistance mechanisms, AZ-6102 exhibits good pharmacokinetics in preclinical species with low Caco2 efflux. Moreover, the compound can be prepared at 20 mg/mL in a clinically meaningful intravenous solution at pH 4 with SBECD acting as an excipient. Future research will examine the in vivo effects of TNKS1 and TNSK2 inhibition on tumor xenografts and normal tissue using AZ-6102 as an intravenous probe compound[2]. |
| Enzyme Assay | In pH 7.5 Tris buffer (60 mM Tris, 1 mM DTT, 0.01% (v/v) Tween-20®, 2.5 mM MgCl2, 0.3 mg/mL BSA), 0.11 μM of tankyrase-1 protein and 3 μM nicotinamide adenine dinucleotide (NAD+, 2.12 μM 3H-NAD+ with a specific radioactivity of 1690 Ci/mol, 0.88 μM biotin-NAD+) are used in the assay. A compound (AZ6102) stock solution (10 mM DMSO) is successively diluted two times in DMSO to determine its IC50. Aliquots of the diluted solutions are then placed into 384-well assay plates and combined with Tankyrase-1 solution. |
| References |
[1]. ACS Med Chem Lett . 2015 Jan 13;6(3):254-9. [2]. ACS Med Chem Lett . 2015 Aug 4;6(9):1019-24. |
Solubility Data
| Solubility (In Vitro) | DMSO: 25~85 mg/mL (58.3~198.35 mM） |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.83 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.83 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.83 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3335 mL | 11.6675 mL | 23.3350 mL | |
| 5 mM | 0.4667 mL | 2.3335 mL | 4.6670 mL | |
| 10 mM | 0.2334 mL | 1.1668 mL | 2.3335 mL |