PROTAC Sirt2 Degrader-1 is a novel, potent PROTAC (proteolysis targeting chimera) which was identified based on the combination of the unique features of the sirtuin rearranging ligands (SirReals) as highly potent and isotype-selective Sirt2 inhibitors with thalidomide, a bona fide cereblon ligand. In its capacity as a Sirt2 degrader, PROTAC Sirt2 Degrader-1 exhibits an IC50 of 0.25 μM for Sirt2, while having no effect on Sirt1/Sirt3 (IC50s > 100 μM). The highly adaptable linking strategy and azide derived from thalidomide can be easily applied to alkynylated ligands of other targets. The HeLa cell undergoes hyperacetylation and enhanced process elongation due to isotype-selective Sirt2 degradation induced by PROTAC Sirt2 Degrader-1. With regard to the ability to chemically induce the degradation of an epigenetic eraser protein, PROTAC Sirt2 Degrader-1 is the first example of a probe.
Physicochemical Properties
| Molecular Formula | C40H40N10O8S2 |
| Molecular Weight | 852.937805175781 |
| Exact Mass | 852.25 |
| Elemental Analysis | C, 56.33; H, 4.73; N, 16.42; O, 15.01; S, 7.52 |
| CAS # | 2098487-75-1 |
| PubChem CID | 135397670 |
| Appearance | White to off-white solid powder |
| LogP | 3.2 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 15 |
| Rotatable Bond Count | 18 |
| Heavy Atom Count | 60 |
| Complexity | 1540 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | GRYRXFYWVDWPQY-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C40H40N10O8S2/c1-23-15-24(2)44-40(43-23)59-22-34(53)46-39-42-18-28(60-39)17-25-7-5-8-27(16-25)57-20-26-19-49(48-47-26)14-4-3-13-41-33(52)21-58-31-10-6-9-29-35(31)38(56)50(37(29)55)30-11-12-32(51)45-36(30)54/h5-10,15-16,18-19,30H,3-4,11-14,17,20-22H2,1-2H3,(H,41,52)(H,42,46,53)(H,45,51,54) |
| Chemical Name | N-[4-[4-[[3-[[2-[[2-(4,6-dimethylpyrimidin-2-yl)sulfanylacetyl]amino]-1,3-thiazol-5-yl]methyl]phenoxy]methyl]triazol-1-yl]butyl]-2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetamide |
| Synonyms | Sirt2-PROTAC-1; Sirt2 PROTAC-1; Sirt2-PROTAC1; Sirt2 PROTAC 1; PROTAC Sirt2 Degrader 1; PROTAC Sirt2 Degrader-1 |
| HS Tariff Code | 2934.99.03.00 |
| 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 | SIRT2 ( IC50 = 0.25 μM ) |
| ln Vitro | In HeLa cells, Sirt2 degradation is induced by PROTAC Sirt2 Degrader-1 (Compound 12; 10 μM, 1-6 hours) [1]. |
| Cell Assay |
Western Blot Analysis[1] Cell Types: HeLa cells Tested Concentrations: 10 µM Incubation Duration: 1-6 hrs (hours) Experimental Results: Causes degradation of Sirt2, but has no effect on Sirt1 levels. |
| References |
[1]. Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals). J Med Chem. 2018 Jan 25;61(2):482-491. |
Solubility Data
| Solubility (In Vitro) | DMSO: ≥ 100 mg/mL (~117.2 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.93 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 (2.93 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 | 1.1724 mL | 5.8621 mL | 11.7242 mL | |
| 5 mM | 0.2345 mL | 1.1724 mL | 2.3448 mL | |
| 10 mM | 0.1172 mL | 0.5862 mL | 1.1724 mL |