Currently Available Strategies for Target Identification of Bioactive Natural Products

Li, Gen; Peng, Xuling; Guo, Yajing; Gong, Shaoxuan; Cao, Shijie; Qiu, Feng

doi:10.3389/fchem.2021.761609

Cited by 25 publications

(14 citation statements)

References 146 publications

(139 reference statements)

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“…However, 6-chloro and 6-methoxy analogues (29−30) showed a slight decreased potency in MIA PaCa-2 cells. In addition, inserting a CH 2 CH 2 O fragment between quinoline and 6-fluoro of 23 retained the cytotoxicity (35). These fluorinated compounds (e.g., 17, 23, and 35) have the potential for developing F-radiolabeled PET imaging ligands.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Phenotypic screening campaigns are especially suited to produce multi-targeted agents with polypharmacology. − A disadvantage of phenotypic screen lies in the challenges in establishing the true direct target(s) of the identified lead inhibitors. − Numerous technologies have been established throughout the years for target identification. Unfortunately, all these methods demand extensive time, resources, and sophisticated instrumentation .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Induction of Genes Implicated in Stress Response and Autophagy by a Novel Quinolin-8-yl-nicotinamide QN523 in Pancreatic Cancer

Kuang

Kyani

et al. 2022

J. Med. Chem.

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Using a cytotoxicity-based phenotypic screen of a highly diverse library of 20,000 small-molecule compounds, we identified a quinolin-8-yl-nicotinamide, QN519, as a promising lead. QN519 represents a novel scaffold with drug-like properties, showing potent in vitro cytotoxicity in a panel of 12 cancer cell lines. Subsequently, lead optimization campaign generated compounds with IC50 values < 1 μM. An optimized compound, QN523, shows significant in vivo efficacy in a pancreatic cancer xenograft model. QN523 treatment significantly increased the expression of HSPA5, DDIT3, TRIB3, and ATF3 genes, suggesting activation of the stress response pathway. We also observed a significant increase in the expression of WIPI1, HERPUD1, GABARAPL1, and MAP1LC3B, implicating autophagy as a major mechanism of action. Due to the lack of effective treatments for pancreatic cancer, discovery of novel agents such as the QN series of compounds with unique mechanism of action has the potential to fulfill a clear unmet medical need.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Induction of Genes Implicated in Stress Response and Autophagy by a Novel Quinolin-8-yl-nicotinamide QN523 in Pancreatic Cancer

Kuang

Kyani

et al. 2022

J. Med. Chem.

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“…[98] In addition to endogenous metabolites, ABPP is a powerful strategy for target identification of natural products. [99] Nomura and colleagues applied the competitive isoTOP-ABPP to profile targets of anti-cancer natural products including nimbolide [100] and withaferin A. [101] Nimbolide was discovered to target an E3 ubiquitin ligase RNF114, which was further furnished for target protein degradation.…”

Section: Development Of Methods Derived From Isotop-abppmentioning

confidence: 99%

“…In addition to endogenous metabolites, ABPP is a powerful strategy for target identification of natural products [99] . Nomura and colleagues applied the competitive isoTOP‐ABPP to profile targets of anti‐cancer natural products including nimbolide [100] and withaferin A [101] .…”

Section: The “Competitive” Isotop‐abppmentioning

confidence: 99%

Quantitative Chemoproteomic Methods for Reactive Cysteinome Profiling

Xiao

Chen

Wang

2023

Israel Journal of Chemistry

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Reactive cysteines often serve as functional sites on proteins and play important regulatory roles in various biological processes. A chemoproteomic method named "isoTOP-ABPP" has enabled global profiling of cysteine reactivity in native systems and greatly increased our understanding on reactive cysteinome. This elegant method and its derived chemoproteomic technologies are now widely applied in profiling of reactive cysteinome and the associated post-translational modifications, discovery of covalent ligands for undruggable targets as well as mechanistic investigation of various biological processes. In this review, we will briefly go over the history of isoTOP-ABPP, summarize recent developments and applications of chemoproteomic technology in reactive cysteinome profiling, and discuss future directions in this field.

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“…Target identification is one of the most crucial steps in drug development. In the past, various strategies for the characterization of drug targets were developed [ 80 , 81 , 82 , 83 ]. These include genomic approaches, phenotypic profiling/screening and biochemical strategies.…”

Section: Secondary Screening: Target-based Assaysmentioning

confidence: 99%

Overview on Strategies and Assays for Antibiotic Discovery

2022

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The increase in antibiotic resistance poses a major threat to global health. Actinomycetes, the Gram-positive bacteria of the order Actinomycetales, are fertile producers of bioactive secondary metabolites, including antibiotics. Nearly two-thirds of antibiotics that are used for the treatment of bacterial infections were originally isolated from actinomycetes strains belonging to the genus Streptomyces. This emphasizes the importance of actinomycetes in antibiotic discovery. However, the identification of a new antimicrobial compound and the exploration of its mode of action are very challenging tasks. Therefore, different approaches that enable the “detection” of an antibiotic and the characterization of the mechanisms leading to the biological activity are indispensable. Beyond bioinformatics tools facilitating the identification of biosynthetic gene clusters (BGCs), whole cell-screenings—in which cells are exposed to actinomycete-derived compounds—are a common strategy applied at the very early stage in antibiotic drug development. More recently, target-based approaches have been established. In this case, the drug candidates were tested for interactions with usually validated targets. This review focuses on the bioactivity-based screening methods and provides the readers with an overview on the most relevant assays for the identification of antibiotic activity and investigation of mechanisms of action. Moreover, the article includes examples of the successful application of these methods and suggestions for improvement.

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Currently Available Strategies for Target Identification of Bioactive Natural Products

Cited by 25 publications

References 146 publications

Induction of Genes Implicated in Stress Response and Autophagy by a Novel Quinolin-8-yl-nicotinamide QN523 in Pancreatic Cancer

Induction of Genes Implicated in Stress Response and Autophagy by a Novel Quinolin-8-yl-nicotinamide QN523 in Pancreatic Cancer

Quantitative Chemoproteomic Methods for Reactive Cysteinome Profiling

Overview on Strategies and Assays for Antibiotic Discovery

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