Drug affinity responsive target stability (DARTS) accelerated small molecules target discovery: Principles and application

Ren, Ying-Shan; Li, Hui-Lin; Piao, Xiu‐Hong; Yang, Zhiyou; Wang, Shumei; Ge, Yue‐Wei

doi:10.1016/j.bcp.2021.114798

Cited by 77 publications

(25 citation statements)

References 103 publications

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“…To confirm the binding of YL-939/YL-939-1 with PHB2 in situ, we performed a label-free small-molecule target identification assay called drug affinity-responsive target stability (DARTS) 38 followed by western blot. It was observed that YL-939/YL-939-1 protected PHB2 from the degradation by pronase, but had no effect on the PHB2 isoform PHB1, as well as VDAC1 and VDAC2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Non-classical ferroptosis inhibition by a small molecule targeting PHB2

Yang

You

et al. 2022

Nat Commun

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Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation. Ferroptosis inhibition is thought as a promising therapeutic strategy for a variety of diseases. Currently, a majority of known ferroptosis inhibitors belong to either antioxidants or iron-chelators. Here we report a new ferroptosis inhibitor, termed YL-939, which is neither an antioxidant nor an iron-chelator. Chemical proteomics revealed the biological target of YL-939 to be prohibitin 2 (PHB2). Mechanistically, YL-939 binding to PHB2 promotes the expression of the iron storage protein ferritin, hence reduces the iron content, thereby decreasing the susceptibility to ferroptosis. We further showed that YL-939 could substantially ameliorate liver damage in a ferroptosis-related acute liver injury model by targeting the PHB2/ferritin/iron axis. Overall, we identified a non-classical ferroptosis inhibitor and revealed a new regulation mechanism of ferroptosis. These findings may present an attractive intervention strategy for ferroptosis-related diseases.

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Section: Resultsmentioning

confidence: 99%

Non-classical ferroptosis inhibition by a small molecule targeting PHB2

Yang

You

et al. 2022

Nat Commun

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“…In this scenario, NPs are recognized as a rich source for developing anti-cancer therapies due to their unique structures and suitable pharmacological profile modulating, for instance, cell cycle and proliferation, cell survival, autophagy, and invasion pathways. Proteomic-based DARTS and LiP approaches are the golden strategies for the identification of the most reliable partners of NPs in complex mixtures of proteins from different cells or tissues, as reported in many recent publications ( Morretta et al, 2021b ; Ren et al, 2021 ). Prompted by our laboratory’s optimization of a DARTS and LiP orthogonal platform, we moved to investigate the interactome of ART in HeLa cancer cells to get a deep understanding of the anti-tumoral profile of this bioactive compound and its more permeable 8-prenylated derivative.…”

Section: Discussionmentioning

confidence: 99%

Drug affinity-responsive target stability unveils filamins as biological targets for artemetin, an anti-cancer flavonoid

Ferraro

Belvedere

Petrella

et al. 2022

Front. Mol. Biosci.

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Artemetin is a valuable 5-hydroxy-3,6,7,3′,4′-pentamethoxyflavone present in many different medicinal plants with very good oral bioavailability and drug-likeness values, owing to numerous bioactivities, such as anti-inflammatory and anti-cancer ones. Here, a multi-disciplinary plan has been settled and applied for identifying the artemetin target(s) to inspect its mechanism of action, based on drug affinity-responsive target stability and targeted limited proteolysis. Both approaches point to the disclosure of filamins A and B as direct artemetin targets in HeLa cell lysates, also giving detailed insights into the ligand/protein-binding sites. Interestingly, also 8-prenyl-artemetin, which is an artemetin more permeable semisynthetic analog, directly interacts with filamins A and B. Both compounds alter filamin conformation in living HeLa cells with an effect on cytoskeleton disassembly and on the disorganization of the F-actin filaments. Both the natural compound and its derivative are able to block cell migration, expectantly acting on tumor metastasis occurrence and development.

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“…It does not modify small molecules and retains its structure to bind directly to targets. 27 The Cellular Thermal Shift Assay (CETSA) is similar to DARTS, not modifying any compound but taking advantage of the thermal stability between the protein and the ligand. Ginsenosides, the active ingredient in Panax ginseng, are considered to have strong biological activity in the central nervous system.…”

Section: T H Imentioning

confidence: 99%

“…Drug Affinity Responsive Target Stability (DARTS) is a common method for finding the targets of chemical compounds. It does not modify small molecules and retains its structure to bind directly to targets . The Cellular Thermal Shift Assay (CETSA) is similar to DARTS, not modifying any compound but taking advantage of the thermal stability between the protein and the ligand.…”

Section: Introductionmentioning

confidence: 99%

Herbicidal Active Compound Ferulic Acid Ethyl Ester Affects Fatty Acid Synthesis by Targeting the 3-Ketoacyl-Acyl Carrier Protein Synthase I (KAS I)

Jia

et al. 2023

J. Agric. Food Chem.

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Exploring new herbicide targets based on natural product derivatives is an important research aspect for the generation of innovative pesticides. Ferulic acid ethyl ester (FAEE), a natural product derivative from ferulic acid, has significant herbicidal activity mainly by inhibiting the normal growth of weed seedling roots. However, the FAEE target protein underlying its herbicidal activity has not been identified. In this study, we synthesized an FAEE probe to locate its site of action. We discovered that FAEE entry point was via the root tips. Fourteen major binding proteins were identified using Drug affinity responsive target stability (DARTS) combined with LC-MS/MS, which included 3-ketoacyl-acyl carrier protein synthase I (KAS I) and phenylalanine ammonia-lyase I (PAL I). The KAS I and PAL I proteins/genes expression was changed significantly after exposure to FAEE, as evidenced by combined transcriptomic and proteomic analysis. A molecular docking assay indicated that KAS I and FAEE had a strong binding ability. Combined with previous studies on FAEE mechanism of action, and based on our results, we conclude that FAEE targeting KAS I lead to the blockage of the fatty acid synthesis pathway and result in plant death.

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Drug affinity responsive target stability (DARTS) accelerated small molecules target discovery: Principles and application

Cited by 77 publications

References 103 publications

Non-classical ferroptosis inhibition by a small molecule targeting PHB2

Non-classical ferroptosis inhibition by a small molecule targeting PHB2

Drug affinity-responsive target stability unveils filamins as biological targets for artemetin, an anti-cancer flavonoid

Herbicidal Active Compound Ferulic Acid Ethyl Ester Affects Fatty Acid Synthesis by Targeting the 3-Ketoacyl-Acyl Carrier Protein Synthase I (KAS I)

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