SMER28 is a small molecule activator (enhancer/modulator) of autophagy that acts via an mTOR-independent mechanism. It induces autophagy independent of rapamycin in mammalian cells and prevents the accumulation of amyloid beta peptide. The hallmarks of Alzheimer's disease are the aggregates of amyloid-β (Αβ) peptide and tau protein. Autophagy is one major cellular pathway leading to the removal of aggregated proteins. Induction of autophagy by small-molecule enhancers such as SMER28 greatly decreased the levels of Aβ peptide (apparent EC50 of ∼10 μM) and APP-CTF (apparent EC50 of ∼20 μM) in a γ-secretase-independent manner. Pharmacological inhibition of autophagy led to a significant accumulation of Aβ peptide and APP-CTF and diminished the effect of SMER28. Therefore, SMER28 may have therapeutic potential to be used for the treatment of Alzheimer's disease and other proteinopathies.
Physicochemical Properties
| Molecular Formula | C11H10BRN3 | |
| Molecular Weight | 264.12 | |
| Exact Mass | 263.006 | |
| Elemental Analysis | C, 50.02; H, 3.82; Br, 30.25; N, 15.91 | |
| CAS # | 307538-42-7 | |
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| PubChem CID | 1560402 | |
| Appearance | Solid powder | |
| Melting Point | 169 °C | |
| LogP | 2.412 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 3 | |
| Rotatable Bond Count | 3 | |
| Heavy Atom Count | 15 | |
| Complexity | 222 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | C=CCNC1=C2C=C(Br)C=CC2=NC=N1 |
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| InChi Key | BCPOLXUSCUFDGE-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C11H10BrN3/c1-2-5-13-11-9-6-8(12)3-4-10(9)14-7-15-11/h2-4,6-7H,1,5H2,(H,13,14,15) | |
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| 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 |
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| 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 | Cell viability in SMER28 (5-200 μM; 24 hours) decreases with dose[4]. |
| ln Vivo | Mice survival is increased at 65 mg/kg of SMER28 (15-65 mg/kg; ih; daily, two days prior to irradiation and over the three days of irradiation) and is strongly protected against post-irradiation weight loss[5]. |
| Cell Assay |
Cell Viability Assay[4] Cell Types: MMS1 cells Tested Concentrations: 5, 25, 50, 75, 100, 150, 200 μM Incubation Duration: 24 hrs (hours) Experimental Results: demonstrated a dose dependent decline of cell viability. |
| Animal Protocol |
Animal/Disease Models: 14 to 16 weeks male mice (Balb/c)[5] Doses: 15, 65 mg/kg Route of Administration: subcutaneous (sc) injection; two days before irradiation and during the three days of irradiation (total 5 days) Experimental Results: Dramatically protected against post- irradiation weight loss and enhanced survival of mice at 65 mg/kg. |
| References |
[1]. Renna M et al. Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative diseases. J Biol Chem. 2010 Apr 9;285(15):11061-7. [2]. Nekova TS, et al. Small molecule enhancers of rapamycin induce apoptosis in myeloma cells via GSK3A/Bpreferentially within a protective bone marrow microenvironment. Br J Haematol. 2014 Oct;167(2):272-4. [3]. Shen D et al. Novel cell- and tissue-based assays for detecting misfolded and aggregated protein accumulation within aggresomes and inclusion bodies. Cell Biochem Biophys. 2011 Jul;60(3):173-85. [4]. Koukourakis MI, et al. SMER28 is a mTOR-independent small molecule enhancer of autophagy that protects mouse bone marrow and liver against radiotherapy. Invest New Drugs. 2018 Oct;36(5):773-781. [5]. Tian Y et al. A small-molecule enhancer of autophagy decreases levels of Abeta and APP-CTF via Atg5-dependent autophagy pathway. FASEB J. 2011 Jun;25(6):1934-42. |
| Additional Infomation | SMER 28 is a member of the class of quinazolines that is quinazoline which is substituted by a prop-2-en-1-ylnitrilo group and a bromo group at positions 4 and 6, respectively. It is a modulator of mammalian autophagy. It has a role as an autophagy inducer. It is a member of quinazolines, a secondary amino compound and an organobromine compound. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.47 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 (9.47 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 (9.47 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 | 3.7862 mL | 18.9308 mL | 37.8616 mL | |
| 5 mM | 0.7572 mL | 3.7862 mL | 7.5723 mL | |
| 10 mM | 0.3786 mL | 1.8931 mL | 3.7862 mL |