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. doi: 10.1021/acs.jmedchem.7b01575.
Liang Ouyang  1 ,  Lan Zhang  1 ,  Shouyue Zhang  1 ,  Dahong Yao  1 ,  Yuqian Zhao  1 ,  Guan Wang  1 ,  Leilei Fu  1 ,  Peng Lei  1 ,  Bo Liu  1
Affiliations
  • 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital , Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu 610041 , China.
PMID: 29561612 DOI: 10.1021/acs.jmedchem.7b01575
Abstract

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.

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