Small-Molecule Activator of UNC-51-Like Kinase 1 (ULK1) That Induces 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). 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.