AUTEN-67, an autophagy-enhancing drug candidate with potent antiaging and neuroprotective effects

Abstract

Autophagy is a major molecular mechanism that eliminates cellular damage in eukaryotic organisms. Basal levels of autophagy are required for maintaining cellular homeostasis and functioning. Defects in the autophagic process are implicated in the development of various age-dependent pathologies including cancer and neurodegenerative diseases, as well as in accelerated aging. Genetic activation of autophagy has been shown to retard the accumulation of damaged cytoplasmic constituents, delay the incidence of age-dependent diseases, and extend life span in genetic models. This implies that autophagy serves as a therapeutic target in treating such pathologies. Although several autophagy-inducing chemical agents have been identified, the majority of them operate upstream of the core autophagic process, thereby exerting undesired side effects. Here, we screened a small-molecule library for specific inhibitors of MTMR14, a myotubularin-related phosphatase antagonizing the formation of autophagic membrane structures, and isolated AUTEN-67 (autophagy enhancer-67) that significantly increases autophagic flux in cell lines and in vivo models. AUTEN-67 promotes longevity and protects neurons from undergoing stressinduced cell death. It also restores nesting behavior in a murine model of Alzheimer disease, without apparent side effects. Thus, AUTEN-67 is a potent drug candidate for treating autophagy-related diseases.

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

“…1627 AUTEN-67 (autophagy enhancer-67): An inhibitor of MTMR14, which enhances macroautophagy. 1628 Autophagic lysosome reformation (ALR): A self-regulating tubulation process in which the macroautophagic generation of nutrients reactivates MTOR, suppresses macroautophagy and allows for the regeneration of lysosomes that were consumed as autolysosomes. 527 See also autolysosome.…”

ER stress and impaired autophagy flux in neuronal degeneration and brain injury

“…Further evidence for autophagy’s role in preventing senescence has been found in a recent study of MTMR14, a myotubularin-related phosphatase, in antagonizing the formation of autophagic membrane structures. Blocking MTMR14 by autophagy enhancer-67 (AUTEN-67) stimulates autophagic flux and increases the lifespan of model organisms (Papp et al, 2016). …”

Roles of autophagy and endoplasmic reticulum stress in intracerebral hemorrhage‐induced secondary brain injury in rats

“…It has also been shown that autophagy is activated after ICH and endoplasmic reticulum (ER) stress occur in neurodegenerative diseases . And autophagy may play different role36s in ischemic and hemorrhagic stroke . However, it is not entirely clear whether ER stress and autophagy are involved in the pathological process of ICH‐induced SBI.…”