Design of Small Molecule Autophagy Modulators: A Promising Druggable Strategy

He, Siyu; Li, Qi; Jiang, Xueyang; Lü, Xin; Feng, Feng; Qu, Wei; Chen, Yao; Sun, Haopeng

doi:10.1021/acs.jmedchem.7b01019

Cited by 34 publications

(28 citation statements)

References 212 publications

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“…Treatment of several solid tumors with 5‐FU or cisplatin can lead to an increased autophagic flux, thus resulting in chemoresistance of the cancer cells against these drugs . Henceforth, based on the stage of the tumor progression, both the inhibition and induction of autophagy may represent promising therapeutic strategies in the fight against cancer …”

Section: Autophagy: Functions and Its Role In Cancermentioning

confidence: 99%

“…Most of the autophagy modulators discovered so far are represented by natural products, or compounds previously employed to act on different biological targets . Lysosomes play a crucial role in the growth and metabolism of the cells.…”

Section: Autophagy Modulators In Oscc and Esccmentioning

confidence: 99%

“…A number of potent autophagy modulators have been identified during the last years, and we herein discuss only the best‐performing representatives. He et al provided a more comprehensive overview which also contains detailed information on key cocrystal structures.…”

Section: Autophagy Modulators In Oscc and Esccmentioning

confidence: 99%

“…Many issues are worthy of future and further investigation, such as the indistinct autophagy‐independent functions of ATGs, the clinically relevant autophagy‐independent activities when targeting the autophagy machinery, possible dose‐ and time‐dependent effects in a clinical setting, and the concentration‐dependent double‐edged sword properties. As poor selectivity (between cancer cells and normal cells) is always a major issue associated to autophagy modulation, diverse strategies should be developed to screen for selective autophagy modulators, including HTS, modification of existing structures, fragment‐based screening, etc . A synergistic combination of medicinal chemistry with molecular biology, chemical biology, structural biology, and cell biology can contribute to the in‐depth understanding of the structural characteristics of autophagy‐related targets.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas

Khan

Relitti

Brindisi

et al. 2019

Medicinal Research Reviews

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Oral squamous cell carcinomas (OSCC) and esophageal squamous cell carcinomas (ESCC) exhibit a survival rate of less than 60% and 40%, respectively. Late-stage diagnosis and lack of effective treatment strategies make both OSCC and ESCC a significant health burden. Autophagy, a lysosome-dependent catabolic process, involves the degradation of intracellular components to maintain cell homeostasis. Targeting autophagy has been highlighted as a feasible therapeutic strategy with clinical utility in cancer treatment, although its associated regulatory mechanisms remain elusive. The detection of relevant biomarkers in biological fluids has been anticipated to facilitate early diagnosis and/or prognosis for these tumors. In this context, recent studies have indicated the presence of specific proteins and small RNAs, detectable in circulating plasma and serum, as biomarkers. Interestingly, the interplay between biomarkers (eg, exosomal microRNAs) and autophagic processes could be exploited in the quest for targeted and more effective therapies for OSCC and ESCC. In this review, we give an overview of the available biomarkers and innovative targeted therapeutic strategies, including the application of autophagy modulators in OSCC and ESCC.Additionally, we provide a viewpoint on the state of the art Tuhina Khan and Nicola Relitti contributed equally to this work. and on future therapeutic perspectives combining the early detection of relevant biomarkers with drug discovery for the treatment of OSCC and ESCC. K E Y W O R D S autophagy, autophagy modulators, biomarkers, esophageal squamous cell carcinoma, exosomes, oral squamous cell carcinoma, targeted therapy 1 | INTRODUCTION Oral squamous cell carcinoma (OSCC) is the predominant malignant neoplasm of the oral cavity followed by verrucous carcinoma, undifferentiated carcinoma, and small salivary adenocarcinoma. 1 Esophageal squamous cell carcinoma (ESCC) is the first histological type and accounts for 80% of cases of esophageal cancer. 2 OSCC and ESCC are indicated as one of the most common cancers by the International Union Against Cancer with an annual incidence of 275 000 and 456 000 cases worldwide, respectively. 3,4 The primary etiology in both OSCC and ESCC is attributed to the environmental factors (tobacco abuse, alcohol consumption), genetic factors (eg, mutations in enzymes), viral factors (human papilloma virus [HPV] infection), and/or the coexistence of these factors. Alcohol intake and tobacco use are responsible for at least 75% of these carcinomas. The underlying initiation and progression mechanisms of OSCC and ESCC are generally characterized by the accumulation of serial epigenetic and genetic alterations, which eventually lead to uncontrolled proliferation of the mutated cells, followed by vigorous cell division. 5,7 Early-stage OSCC detection displays an 80% survival rate at 5 years, while detection at advanced stage leads to survival rates ranging from 20% to 40%. 6 In ESCC, the 5-year survival rate for early-stage detection may reach 85%, whereas a dr...

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Section: Autophagy: Functions and Its Role In Cancermentioning

confidence: 99%

Section: Autophagy Modulators In Oscc and Esccmentioning

confidence: 99%

Section: Autophagy Modulators In Oscc and Esccmentioning

confidence: 99%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

See 2 more Smart Citations

Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas

Khan

Relitti

Brindisi

et al. 2019

Medicinal Research Reviews

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“…Design of small‐molecule autophagy modulators therefore appears to be a promising druggable strategy . Among these, ARP101, originally characterized for its inhibitory property against matrix metalloproteinase 2 (MMP‐2) catalytic functions, was found to also trigger autophagy in cells of mouse embryo fibroblasts .…”

Section: Introductionmentioning

confidence: 99%

Dual functions of ARP101 in targeting membrane type‐1 matrix metalloproteinase: Impact on U87 glioblastoma cell invasion and autophagy signaling

Desjarlais

Annabi

2018

Chem Biol Drug Des

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Abbreviations: ATG, autophagy-related proteins; ConA, concanavalin-A; ECM, extracellular matrix; MT1-MMP, membrane type-1 matrix metalloproteinase. Abstract Membrane type-1 matrix metalloproteinase (MT1-MMP) possesses both extracellular proteolytic and intracellular signal-transducing functions in tumorigenesis. An imbalance in MT1-MMP expression and/or function triggers a metastatic, invasive, and therapy resistance phenotype. MT1-MMP is involved in extracellular matrix (ECM) proteolysis, activation of latent MMPs, as well as in autophagy signaling in human hepatoma and glioblastoma cells. A low autophagy index in tumorigenesis has been inferred by recent studies where autophagic capacity was decreased during tumor progression. Here, we establish ARP101 as a dual-function small-molecule inhibitor against MT1-MMP ECM hydrolysis and autophagy signal-transducing functions in a model of grade IV glioblastoma cells. ARP101 inhibited concanavalin-A-mediated proMMP-2 activation into MMP-2, as well as MT1-MMP auto-proteolytic processing. When overexpressing recombinant Wt MT1-MMP, ARP101 inhibited proMMP-2 activation and triggered the formation of MT1-MMP oligomers that required trafficking to the plasma membrane. ARP101 further induced cell autophagy as reflected by increased formation of acidic vacuole organelles, LC3 puncta, and autophagy-related protein ATG9 transcription. These were all significantly reversed upon siRNA-mediated gene silencing of MT1-MMP. ARP101 can thus concomitantly inhibit MT1-MMP extracellular catalytic function and exploit its intracellular transducing signal function to trigger autophagy-mediated cell death in U87 glioblastoma cancer cells. K E Y W O R D S ARP101, autophagy, concanavalin-A, glioblastoma, MT1-MMP processing How to cite this article: Desjarlais M, Annabi B. Dual functions of ARP101 in targeting membrane type-1 matrix metalloproteinase: Impact on U87 glioblastoma cell invasion and autophagy signaling. Chem Biol Drug Des. 2019;93:272-282. https://doi.

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Phenotyping Reveals Targets of a Pseudo‐Natural‐Product Autophagy Inhibitor

et al. 2020

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Pseudo‐natural‐product (NP) design combines natural product fragments to provide unprecedented NP‐inspired compounds not accessible by biosynthesis, but endowed with biological relevance. Since the bioactivity of pseudo‐NPs may be unprecedented or unexpected, they are best evaluated in target agnostic cell‐based assays monitoring entire cellular programs or complex phenotypes. Here, the Cinchona alkaloid scaffold was merged with the indole ring system to synthesize indocinchona alkaloids by Pd‐catalyzed annulation. Exploration of indocinchona alkaloid bioactivities in phenotypic assays revealed a novel class of azaindole‐containing autophagy inhibitors, the azaquindoles. Subsequent characterization of the most potent compound, azaquindole‐1, in the morphological cell painting assay, guided target identification efforts. In contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation‐ and rapamycin‐induced autophagy by targeting the lipid kinase VPS34.

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Design of Small Molecule Autophagy Modulators: A Promising Druggable Strategy

Cited by 34 publications

References 212 publications

Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas

Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas

Dual functions of ARP101 in targeting membrane type‐1 matrix metalloproteinase: Impact on U87 glioblastoma cell invasion and autophagy signaling

Phenotyping Reveals Targets of a Pseudo‐Natural‐Product Autophagy Inhibitor

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