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Purity: ≥98%
BL-918, a racemic mixture, is a novel and potent small molecule activator of UNC-51-like kinase 1 (ULK1), inducing cytoprotective autophagy for Parkinson’s disease treatment. UNC-51-like kinase 1 (ULK1), the yeast Atg1 ortholog, is the sole serine-threonine kinase and initiating enzyme in autophagy, which may be regarded as a target in Parkinson's disease (PD). 33i (BL-918) as a potent activator of ULK1 by structure-based drug design. Subsequently, some key amino acid residues (Arg18, Lys50, Asn86, and Tyr89) were found to be crucial to the binding pocket between ULK1 and 33i by site-directed mutagenesis. Moreover, it was found that 33i induced autophagy via the ULK complex in SH-SY5Y cells. Intriguingly, this activator displayed a cytoprotective effect on MPP+-treated SH-SY5Y cells, as well as protected against MPTP-induced motor dysfunction and loss of dopaminergic neurons by targeting ULK1-modulated autophagy in mouse models of PD. Together, these results demonstrate the therapeutic potential to target ULK1, and 33i, the novel activator of ULK1, may serve as a candidate drug for future PD treatment.
| ln Vitro |
BL-918 (compound 33i) exhibits a high binding affinity for ULK1 (KD=0.719 μM) [1]. In neuronal-like SH-SY5Y cells, BL-918 (5 μM) induces autophagy over a 24-hour period [1]. -918 (0.5-50 μM; 24 hours) partially reverses MPP+-induced cell death, as determined by enhancing cell viability [1]. BL-918 (5 μM; duration 6-36 hours) time-drivenly increases the expression levels and phosphorylation status of LC3-II and Beclin-1, while reducing the levels of the autophagy substrate SQSTM1/p62. BL-918 increases the phosphorylation of ULK1 at Ser317 and Ser555, and decreases the phosphorylation of ULK1 at Ser757 [1]. Cell Autophagy Assay[1]
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| ln Vivo |
Compound 33i, also known as BL-918 (compound 20, 40, or 80 mg/kg/day; border gavage; started two days prior to the first saline/MPTP injection and continued for five days following the last saline/MPTP injection), dramatically lowers dopamine (DA), homovanillic acid (HVA), and 3,4-diphenyl acetamide (DOPAC) levels [1].
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| Cell Assay |
Cell Autophagy Assay[1]
Cell Types: SH-SY5Y cells Tested Concentrations: 5 μM Incubation Duration: For 24 hrs (hours) Experimental Results: Induced autophagy. Cell viability assay [1] Cell Types: SH-SY5Y Cell Tested Concentrations: 0.5, 5, 50 μM Incubation Duration: 24 hrs (hours) Experimental Results: MPP+-induced cell death can be partially reversed, as determined by enhanced cell viability. Western Blot Analysis[1] Cell Types: SH-SY5Y Cell Tested Concentrations: 5 μM Incubation Duration: 6, 12, 24, 36 hrs (hours) Experimental Results: Time-dependent increase in the expression of LC3-II (key marker of autophagy), Beclin level-1 and its phosphorylation status, thereby reducing the levels of the selective autophagy substrate SQSTM1/p62. |
| Animal Protocol |
Animal/Disease Models: Male C57BL/6 mice (eight weeks old) weighing between 20 and 25 g [1]
Doses: 20, 40 or 80 mg/kg Route of Administration: po (oral gavage); daily; first time Start 2 days before injecting saline/MPTP and continue for 5 days after the last injection of saline/MPTP. Experimental Results: Reduce the loss of DA and its metabolites. |
| References |
[1]. Ouyang L, et al. Small-Molecule Activator of UNC-51-Like Kinase 1 (ULK1) That Induces Cytoprotective Autophagy for Parkinson's Disease Treatment. J Med Chem. 2018 Apr 12;61(7):2776-2792.
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| Molecular Formula |
C23H15F8N3OS
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| Molecular Weight |
533.4369
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| CAS # |
2101517-69-3
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| Related CAS # |
(Rac)-BL-918;2435589-07-2
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| SMILES |
O=C(NC1=CC=C(F)C=C1F)C(NC(NC2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2)=S)C3=CC=CC=C3O
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| Synonyms |
BL-918; BL 918; BL918
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| 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)
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| Solubility (In Vitro) |
DMSO : ≥ 250 mg/mL (~468.66 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.90 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 20.8 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 | 1.8746 mL | 9.3731 mL | 18.7463 mL | |
| 5 mM | 0.3749 mL | 1.8746 mL | 3.7493 mL | |
| 10 mM | 0.1875 mL | 0.9373 mL | 1.8746 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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