Small-Molecule Activator of UNC-51-Like Kinase 1 (ULK1) That Induces Cytoprotective Autophagy for Parkinson's Disease Treatment.
Liang OuyangLan ZhangShouyue ZhangDahong YaoYuqian ZhaoGuan WangLeilei FuPeng LeiBo LiuPublished in: Journal of medicinal chemistry (2018)
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). Herein, we discovered a small molecule 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, we 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.
Keyphrases
- small molecule
- induced apoptosis
- endoplasmic reticulum stress
- cell death
- oxidative stress
- signaling pathway
- protein kinase
- cell cycle arrest
- nuclear factor
- amino acid
- tyrosine kinase
- drug induced
- high glucose
- mouse model
- current status
- spinal cord injury
- pi k akt
- transcription factor
- cell proliferation
- saccharomyces cerevisiae
- smoking cessation