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Diverse Compounds from Pleuromutilin Lead to a Thioredoxin Inhibitor and Inducer of Ferroptosis

ABSTRACT: Diverse Compounds from Pleuromutilin Lead to a Thioredoxin Inhibitor and Inducer of Ferroptosis

PROVIDER: PRJNA523577 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8602370.fastq.gz	Fastqsanger.gz
	SRR8602371.fastq.gz	Fastqsanger.gz
	SRR8602364.fastq.gz	Fastqsanger.gz
	SRR8602365.fastq.gz	Fastqsanger.gz
	SRR8602366.fastq.gz	Fastqsanger.gz

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Diverse Compounds from Pleuromutilin Lead to a Thioredoxin Inhibitor and Inducer of Ferroptosis

Project description:The chemical diversification of natural products provides a robust and general method for creation of stereochemically rich and structurally diverse small molecules. The resulting compounds have physicochemical traits different from those in most screening collections, and as such are an excellent source for biological discovery. Herein, we subject the diterpene natural product pleuromutilin to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in a collection of compounds with previously unreported ring systems, providing a novel set of structurally diverse and highly complex compounds suitable for screening in a variety of different settings. Biological evaluation identified the novel compound ferroptocide, a small molecule that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR knockout studies reveal that ferroptocide is an inhibitor of thioredoxin, a key component of the antioxidant system in the cell. Ferroptocide positively modulates the immune system in a murine model of breast cancer and will be a useful tool to study the utility of pro-ferroptotic agents for treatment of cancer.

2019-04-22 | GSE126868 | GEO

Diverse Compounds from Pleuromutilin Lead to a Thioredoxin Inhibitor and Inducer of Ferroptosis

Project description:The chemical diversification of natural products provides a robust and general method for creation of stereochemically complex and structurally diverse small molecules. The resulting compounds have physicochemical traits different from those in most screening collections, and as such are a rich source for biological discovery. Herein, we subject the terpene natural product pleuromutilin to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in the synthesis of multiple compounds with previously unreported ring systems, providing a set of novel structurally diverse and highly complex compounds suitable for screening in a variety of different settings. Biological evaluation of these compounds identified the novel compound ferroptocide, a compound that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR KO studies reveal that ferroptocide is an inhibitor of thioredoxin, a key component of thioredoxin antioxidant system in the cell. Ferroptocide shows the ability to positively modulate the immune system in a murine model of breast cancer and will be a useful tool to study the ability of pro-ferroptotic agents to synergize with the immune system for treatment of cancer.

2020-05-26 | PXD012805 | Pride

Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis.

Project description:The chemical diversification of natural products provides a robust and general method for the creation of stereochemically rich and structurally diverse small molecules. The resulting compounds have physicochemical traits different from those in most screening collections, and as such are an excellent source for biological discovery. Herein, we subject the diterpene natural product pleuromutilin to reaction sequences focused on creating ring system diversity in few synthetic steps. This effort resulted in a collection of compounds with previously unreported ring systems, providing a novel set of structurally diverse and highly complex compounds suitable for screening in a variety of different settings. Biological evaluation identified the novel compound ferroptocide, a small molecule that rapidly and robustly induces ferroptotic death of cancer cells. Target identification efforts and CRISPR knockout studies reveal that ferroptocide is an inhibitor of thioredoxin, a key component of the antioxidant system in the cell. Ferroptocide positively modulates the immune system in a murine model of breast cancer and will be a useful tool to study the utility of pro-ferroptotic agents for treatment of cancer.

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Project description:Transcriptomic study of a thioredoxin reductase knock-out mutant. Biological question : Thioredoxins are small redox proteins implicated in crucial pathways of cell life. They are reduced by a conserved flavoprotein named NADPH-dependent thioredoxin reductase (NTR). In order to give an insight into the functions of the NTR/thioredoxin pathway in Arabidopsis, we have used a reverse genetic approch. Both NTR genes (NTRA and NTRB) have been inactivated in the double ntra ntrb mutant. T-DNA lines have been provided by the SALK library. Surprisingly, this mutant shows a limited phenotype suggested that some additional redox pathways are involved in compensating the inactivation of the NTR/thioredoxin pathway. In order to isolate compensatory genes that would be transcriptionally induced in the ntra ntrb mutant, we have performed this CATMA project. Seeds of the wild-type Col-0 ecotype and of the ntra ntrb homozygote double mutant were sowed in soil. Three replicates of lines were made (Col-0 1, 2 and 3 ntra ntrb 1, 2 and 3) : plants were put at different places of the greenhouse and grown at different times. Germination was synchronized by 4 days at 4C and plants were grown during 17 days, until they reached a 6 rosette leaves stage. Entire plants (30 plants per sample) were harvested, frozen in liquid nitrogen and stored at -80C until extraction.

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