Small-Molecule Activator of UNC-51-Like Kinase 1 (ULK1) That Induces Cytoprotective Autophagy for Parkinson’s Disease Treatment

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.

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

“…The induction of protective autophagy to inhibit apoptosis is one of the reasons for the development of drug resistance in tumor cells during therapy [207]. Some small molecule drugs targeting ULK1 show inhibitory effects on ULK1 expression and the activity of autophagy, and cause tumor cells to be more sensitive to chemotherapeutic drugs [136,208]. It has been reported that overexpression of ULK1 is inversely related to the prognosis of various tumors, such as colon cancer, breast cancer, lung cancer, nasopharyngeal cancer, and esophageal cancer [136].…”

Exosomes derived from mesenchymal stem cells repair a Parkinson’s disease model by inducing autophagy

“…Autophagy is a cellular mechanism that recycles materials such as abnormal proteins and damaged organelles to maintain cell survival and homeostasis. The alteration of autophagy may be a key factor contributing to the pathogenesis of PD 15 , and a number of reports showed that increased autophagy has potential therapeutic effects in PD 16,17 . In the present study, we investigated whether and how Exos repair the damage of PD models in vitro and in vivo by regulating autophagy.…”

Stem Cell Therapy: Curcumin Does the Trick

“…In recent years, several pieces of evidence suggest that autophagy plays an important role in neurogenic disorders, such as HD, PD, Alzheimer's, and amyotrophic lateral sclerosis (Karabiyik, Lee, & Rubinsztein, 2017;Ouyang et al, 2018;Shi et al, 2012). However, other studies have shown that excessive autophagy could be related to neuronal death in cerebral ischemia (Fornai et al, 2008;Kabuta, Suzuki, & Wada, 2006;Shi et al, 2012).…”