Small molecule probes for targeting autophagy

Whitmarsh-Everiss, Thomas; Laraia, Luca

doi:10.1038/s41589-021-00768-9

Cited by 70 publications

(79 citation statements)

References 101 publications

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“…Thus, inhibition of PPT1 results in autophagy inhibition. In addition, lysosomal function and/or fusion with autophagosomes could be targeted by other means of pH regulation (such as via modulation of V-ATPase), inhibition of the cation channel TRPML1, inhibition of lysosomal enzymes or modulation of lysosomal membrane dynamics — fusion and fission — which impact on lysosomal number and function 179 , 180 , 183 , 204 (Table 1 ).…”

Section: Therapeutic Interventionsmentioning

confidence: 99%

Machinery, regulation and pathophysiological implications of autophagosome maturation

Zhao

Codogno

Zhang

2021

Nat Rev Mol Cell Biol

294

197

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Cells in multicellular organisms constantly experience diverse stresses, including protein misfolding, organelle damage, scarcity of nutrients/energy and invasion by pathogens. One mechanism exploited by cells to combat stresses is the lysosome-mediated degradation of intracellular components via autophagy. Autophagy involves the formation of an isolation membrane (or phagophore), which further expands and closes to form the double-membrane autophagosome 1-3 . The mechanism of autophagosome formation was excellently reviewed recently 3 . Various cellular materials can be sequestered in autophagosomes, including unselected cytosolic material or selected cargos such as protein aggregates, damaged organelles and pathogens. Following autophagosome closure via membrane abscission, cargos are delivered to the vacuole (yeasts and plants) or to lysosomes (animal cells) (for an overview of the autophagy process see [4][5][6][7][8] ; Box 1). After degradation of the autophagic cargo, the digested content in the autolysosomes is released and lysosomes are re-formed to sustain the autophagic flux (Box 2). A series of proteins encoded by ATG (autophagy-related) genes and EPG (ectopic PGL granules) genes -identified mainly from genetic screens in Saccharomyces cerevisiae and Caenorhabditis elegans, respectively -act at different membrane remodelling steps for autophagosome formation and maturation 3,4,9,10 .In yeast, autophagosomes are formed in the vicinity of and directly fuse with the much larger vacuole, whereas in multicellular organisms, newly formed autophagosomes fuse with different endolysosomal vesicles such as early/late endosomes and lysosomes to form non-degradative, single-membrane structures called 'amphisomes' , which gradually acquire

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Section: Therapeutic Interventionsmentioning

confidence: 99%

Machinery, regulation and pathophysiological implications of autophagosome maturation

Zhao

Codogno

Zhang

2021

Nat Rev Mol Cell Biol

294

197

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“…Similarly, blocking autophagy by targeting ATGs (i.e., ULK1 or VPS34) can have off-target effects, since these genes also have autophagy unrelated functions. Nevertheless, autophagic inhibitors are commonly used to block autophagy in experimental settings, while CQ and HCQ are compounds also used in the clinic [15][16][17][18][19][20].…”

Section: Autophagymentioning

confidence: 99%

The Multifaceted Functions of Autophagy in Breast Cancer Development and Treatment

Niklaus

Tokarchuk

Zbinden

et al. 2021

Cells

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Macroautophagy (herein referred to as autophagy) is a complex catabolic process characterized by the formation of double-membrane vesicles called autophagosomes. During this process, autophagosomes engulf and deliver their intracellular content to lysosomes, where they are degraded by hydrolytic enzymes. Thereby, autophagy provides energy and building blocks to maintain cellular homeostasis and represents a dynamic recycling mechanism. Importantly, the clearance of damaged organelles and aggregated molecules by autophagy in normal cells contributes to cancer prevention. Therefore, the dysfunction of autophagy has a major impact on the cell fate and can contribute to tumorigenesis. Breast cancer is the most common cancer in women and has the highest mortality rate among all cancers in women worldwide. Breast cancer patients often have a good short-term prognosis, but long-term survivors often experience aggressive recurrence. This phenomenon might be explained by the high heterogeneity of breast cancer tumors rendering mammary tumors difficult to target. This review focuses on the mechanisms of autophagy during breast carcinogenesis and sheds light on the role of autophagy in the traits of aggressive breast cancer cells such as migration, invasion, and therapeutic resistance.

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“…[1] In addition to their roles in cholesterol transport, CTPs have been demonstrated to regulate organelle contact sites,c ellular metabolism, degradative pathways such as autophagy,a nd viral entry. [2][3][4][5][6][7] CTPs have thus been implicated and proposed as targets for the treatment of neurodegenerative disorders,v iral infections,a sw ell as numerous types of cancer. Despite the clear biological importance of these CTPs,v ery few selective inhibitors of these proteins are known, in part due to the inherent difficulties of targeting their structurally related cholesterol binding domains.T herefore,t he identification of selective inhibitors of CTPs would enable the further study and therapeutic targeting of sterol-mediated processes.T he identification of novel bioactive small molecules has in recent years seen at rend towards the use of natural product (NP)like collections of high predicted biological diversity.…”

Section: Introductionmentioning

confidence: 99%

Identification of Inhibitors of Cholesterol Transport Proteins Through the Synthesis of a Diverse, Sterol‐Inspired Compound Collection

2021

Self Cite

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Cholesterol transport proteins regulate av ast array of cellular processes including lipid metabolism, vesicular and non-vesicular trafficking,o rganelle contact sites,a nd autophagy.D espite their undoubted importance,t he identification of selective modulators of this class of proteins has been challenging due to the structural similarities in the cholesterol-binding site.H erein we report ag eneral strategy for the identification of selective inhibitors of cholesterol transport proteins via the synthesis of adiverse sterol-inspired compound collection. Fusion of ap rimary sterol fragment to an arrayo f secondary privileged scaffolds led to the identification of potent and selective inhibitors of the cholesterol transport protein Aster-C,w hich displayed as urprising preference for the unnatural-sterol AB-ring stereochemistry and new inhibitors of Aster-A. We propose that this strategy can and should be applied to any therapeutically relevant sterol-binding protein.

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Small molecule probes for targeting autophagy

Cited by 70 publications

References 101 publications

Machinery, regulation and pathophysiological implications of autophagosome maturation

Machinery, regulation and pathophysiological implications of autophagosome maturation

The Multifaceted Functions of Autophagy in Breast Cancer Development and Treatment

Identification of Inhibitors of Cholesterol Transport Proteins Through the Synthesis of a Diverse, Sterol‐Inspired Compound Collection

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