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Oxaboroles target trypanosome CPSF3

ABSTRACT: Oxaboroles target trypanosome CPSF3 - SCYX-6759 screen

PROVIDER: PRJEB25885 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR2497832_1.fastq.gz	Fastqsanger.gz
	ERR2497832_2.fastq.gz	Fastqsanger.gz

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Oxaboroles target trypanosome CPSF3

Project description:Oxaboroles target trypanosome CPSF3 - DDD85646 screen

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CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone mRNA processing

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target Cleavage and Polyadenylation Specificity Factor 3 (CPSF3), the 3’ endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation of non-transformed immortalized control pancreatic cells. Mechanistically, JTE-607 induces transcriptional read-through in replication-dependent histones, reduces core histone expression, destabilizes chromatin structure and arrests cells in the S-phase of the cell cycle. Therefore, CPSF3 represents a potential therapeutic target for the treatment of PDAC.

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Function of Trypanosome brucei RBP10

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Clinical and veterinary trypanocidal benzoxaboroles target CPSF3.

Project description:African trypanosomes cause lethal and neglected tropical diseases, known as sleeping sickness in humans and nagana in animals. Current therapies are limited, but fortunately, promising therapies are in advanced clinical and veterinary development, including acoziborole (AN5568 or SCYX-7158) and AN11736, respectively. These benzoxaboroles will likely be key to the World Health Organization's target of disease control by 2030. Their mode of action was previously unknown. We have developed a high-coverage overexpression library and use it here to explore drug mode of action in Trypanosoma brucei Initially, an inhibitor with a known target was used to select for drug resistance and to test massive parallel library screening and genome-wide mapping; this effectively identified the known target and validated the approach. Subsequently, the overexpression screening approach was used to identify the target of the benzoxaboroles, Cleavage and Polyadenylation Specificity Factor 3 (CPSF3, Tb927.4.1340). We validated the CPSF3 endonuclease as the target, using independent overexpression strains. Knockdown provided genetic validation of CPSF3 as essential, and GFP tagging confirmed the expected nuclear localization. Molecular docking and CRISPR-Cas9-based editing demonstrated how acoziborole can specifically block the active site and mRNA processing by parasite, but not host CPSF3. Thus, our findings provide both genetic and chemical validation for CPSF3 as an important drug target in trypanosomes and reveal inhibition of mRNA maturation as the mode of action of the trypanocidal benzoxaboroles. Understanding the mechanism of action of benzoxaborole-based therapies can assist development of improved therapies, as well as the prediction and monitoring of resistance, if or when it arises.

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Target identification of an antimalarial oxaborole identifies AN13762 as an alternative chemotype for targeting CPSF3 in apicomplexan parasites.

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Project description:Monodelphis domestica CPSF3, cleavage and polyadenylation specific factor 3 [Source:NCBI gene;Acc:100028117], is expressed in 1 baseline experiment(s);

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Project description:Sus scrofa CPSF3, cleavage and polyadenylation specific factor 3 [Source:VGNC Symbol;Acc:VGNC:86960], is differentially expressed in 3 experiment(s);

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