BL-918 is an activator of UNC-51-like kinase 1 (ULK1; EC50=24.14nM). BL-918 can induce cytoprotective autophagy by targeting the ULK complex, while increasing ULK1 phosphorylation at Ser317 and Ser555 and decreasing phosphorylation at Ser757 to activate the autophagy pathway. BL-918 can be used in research related to Parkinson's disease and amyotrophic lateral sclerosis[1-4].
In vitro, BL-918 (0.5–5μM) was used to treat SH-SY5Y cells for 6 hours. BL-918 significantly enhanced cell viability and induced cytoprotective autophagy[5]. BL-918 (20μM) was co-treated with 6-OHDA (50μM) or 1-methyl-4-phenylpyridinium (1mM) in SH-SY5Y cells for 24 hours. BL-918 significantly attenuated neurotoxicity and protected mitochondrial function[6].
In vivo, BL-918 (40 or 80mg/kg; twice daily by oral gavage) was administered to SODG93A mice for 46 weeks. BL-918 dose-dependently extended lifespan and improved motor function[7]. BL-918 (40mg/kg; once daily orally) was used to treat an MPTP (25mg/kg; once daily intraperitoneal injection; days 3–7)-induced Parkinson's disease mouse model for 12 days. BL-918 significantly improved motor function and alleviated the loss of dopaminergic neurons, and these effects were PINK1-dependent[8].
References:
[1] Yang J, Wu Q, Li Y, et al. BL-918 alleviates oxidative stress in rats after subarachnoid hemorrhage by promoting mitophagy through the ULK1/PINK1/Parkin pathway. Free Radic Biol Med. 2024 Nov 1;224:846-861.
[2] Anjum F, Hawsawi N, Almalki AA, et al. Exploring bioactive phytochemicals as ULK1 activators for enhancing cytoprotective autophagy in amyotrophic lateral sclerosis. Front Pharmacol. 2025 Sep 4;16:1661744.
[3] Zhang L, He C, Liu Z, et al. Benfotiamine, a Lipid-Soluble Derivative of Vitamin B1, Ameliorates the Carbohydrate Overload-Induced Mitochondrial Dysfunction in Fish Megalobrama amblycephala by Triggering the ULK1-Mediated Mitophagy. Aquac Nutr. 2025 May 1;2025:7688386.
[4] Gong Y, Deng Z, Wu J, et al. Ferrodoxin 1 (FDX1) drives paclitaxel resistance in ovarian cancer via copper metabolism and ULK1/ATG13-mediated autophagy: overcome by pH/ROS-responsive PPD/PDP@si-FDX1 nanomicelles. J Exp Clin Cancer Res. 2026 Apr 23;45(1):104.
[5] Ouyang L, Zhang L, Zhang S, 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.
[6] Lee C, Kim DY, Kim SM, et al. HUWE1 regulates mitophagy to protect dopaminergic neurons from 6-OHDA- and MPP⁺-induced neurotoxicity. Cell Biol Toxicol. 2026 Feb 5;42(1):34.
[7] Liu W, Zhu SO, Guo YL, et al. BL-918, a small-molecule activator of ULK1, induces cytoprotective autophagy for amyotrophic lateral sclerosis therapy. Acta Pharmacol Sin. 2023 Mar;44(3):524-537.
[8] Wang Y, Luo S, Su H, et al. BL-918 activates PINK1/Parkin signaling pathway to ameliorate the progression of Parkinson's disease. J Biol Chem. 2024 Aug;300(8):107543.