ARN-3236 (ARN3236) is a novel, potent, oral bioavailable and selective inhibitor of salt-inducible kinase 2 (SIK2) with anticancer activity. It inhibits SIK2 with IC50s of<1 nM, 21.63 nM and 6.63 nM for SIK2, SIK1 and SIK3, respectively. SIK2 is overexpressed in approximately 30% of high-grade serous ovarian cancers. ARN-3236 inhibited the growth of 10 ovarian cancer cell lines at an IC50 of 0.8 to 2.6 μmol/L, where the IC50 of ARN-3236 was inversely correlated with endogenous SIK2 expression (Pearson r = -0.642, P = 0.03). ARN-3236 enhanced sensitivity to paclitaxel in 8 of 10 cell lines, as well as in SKOv3ip (P = 0.028) and OVCAR8 xenografts. In at least three cell lines, a synergistic interaction was observed. ARN-3236 uncoupled the centrosome from the nucleus in interphase, blocked centrosome separation in mitosis, caused prometaphase arrest, and induced apoptotic cell death and tetraploidy. ARN-3236 also inhibited AKT phosphorylation and attenuated survivin expression. ARN-3236 is the first orally available inhibitor of SIK2 to be evaluated against ovarian cancer in preclinical models and shows promise in inhibiting ovarian cancer growth and enhancing paclitaxel chemosensitivity.
Physicochemical Properties
| Molecular Formula | C19H16N2O2S |
| Molecular Weight | 336.407543182373 |
| Exact Mass | 336.093 |
| CAS # | 1613710-01-2 |
| Related CAS # | 1613710-01-2 (HCl) |
| PubChem CID | 74766530 |
| Appearance | White to off-white solid powder |
| LogP | 4.2 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 24 |
| Complexity | 424 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | S1C=CC(=C1)C1C=CN=C2C=1C(=CN2)C1C=CC(=CC=1OC)OC |
| InChi Key | WEHOIIGXTMKVRG-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C19H16N2O2S/c1-22-13-3-4-15(17(9-13)23-2)16-10-21-19-18(16)14(5-7-20-19)12-6-8-24-11-12/h3-11H,1-2H3,(H,20,21) |
| Chemical Name | 3-(2,4-Dimethoxyphenyl)-4-(3-thienyl)-1H-pyrrolo[2,3-b]pyridine |
| Synonyms | ARN3236; ARN 3236; ARN-3236. |
| 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
| ln Vitro | At IC50 <1 nM, ARN-3236 suppresses SIK2 activity[2]. Ovarian cancer cell proliferation is inhibited and NSC 125973 sensitivity is increased by ARN-3236 [2]. |
| ln Vivo | ARN-3236 (60 mg/kg, oral) makes ovarian cancer more susceptible to NSC 125973 in vivo [2]. |
| Cell Assay |
Cell viability assay [2] Cell Types: HEY and A2780 human ovarian cancer cell lines. Tested Concentrations: 0-10μM. Incubation Duration: 24 hrs (hours). Experimental Results: Inhibits SIK2 activity, IC50 <1 nM. |
| Animal Protocol |
Animal/Disease Models: SKOv3ip mice and OVCAR8 mice [2]. Doses: 60 mg/kg. Route of Administration: Orally one time/day for 3 weeks (SKOv3ip-carrying mice) and 4 weeks (OVCAR8-carrying mice). Experimental Results: Ovarian cancer is sensitive to NSC 125973. |
| References |
[1]. SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotype. J Leukoc Biol. 2016 May;99(5):711-21. [2]. A Novel Compound ARN-3236 Inhibits Salt-Inducible Kinase 2 and Sensitizes Ovarian Cancer Cell Lines and Xenografts. Clin Cancer Res. 2017 Apr 15;23(8):1945-1954. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~50 mg/mL (~148.63 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.17 mg/mL (6.45 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 21.7 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: ≥ 2.17 mg/mL (6.45 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 21.7 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: ≥ 2.17 mg/mL (6.45 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 21.7 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 | 2.9726 mL | 14.8628 mL | 29.7256 mL | |
| 5 mM | 0.5945 mL | 2.9726 mL | 5.9451 mL | |
| 10 mM | 0.2973 mL | 1.4863 mL | 2.9726 mL |