Author: Schwarz, Carla D ; Maraszek, Kathryn E ; Gurova, Katerina V ; Yalamanchili, Hari Krishna ; Gomez, Eduardo Cortes ; Jonnakuti, Venkata S ; Cornwell, Abigail C ; Tisdale, Arwen A ; Chaubey, Aditi H ; Kim, Minsuh ; Paterson, Emily J ; Wang, Jianmin ; Alahmari, Abdulrahman A ; Feigin, Michael E ; Venkat, Swati

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 thatCPSF3is highly expressed in PDAC and is associated with poor prognosis.CPSF3knockdown 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 nontransformed immortalized control pancreatic cells. Mechanistically, JTE-607 induces transcriptional readthrough 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.

01 Jan 2020·Nature Chemical Biology

CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing’s sarcoma

Article

Author: Jenkins, Jeremy ; Saran, Chitra ; Thomas, Jason R ; Schuierer, Sven ; Beckwith, Rohan E J ; Williams, Eric T ; Weihofen, Wilhelm A ; Carl, Sarah H ; Artus-Revel, Caroline G ; Gleim, Scott ; Fazal, Aleem ; Reece-Hoyes, John S ; George, Elizabeth L ; Tallarico, John ; Schirle, Markus ; Molind, Gregory J ; Xie, Kevin ; Carbone, Walter ; Roma, Guglielmo ; Chao, Jeffrey A ; Turner, Jonathan ; Brittain, Scott M ; Chen, Aye ; Lohmann, Felix ; Knehr, Judith ; Wang, Yuan ; Salcius, Michael ; Boynton, Geoffrey ; Miller, Howard R ; Zambrowski, Mark ; Carbonneau, Seth ; Akinjiyan, Favour A ; Michaud, Gregory ; Sigoillot, Frederic ; Ross, Nathan T ; Henault, Martin ; Passmore, Lori A ; Rodríguez-Molina, Juan B ; Jia, Min ; Spencer, Matt ; Murphy, Jason ; Wilbertz, Johannes H

The post-genomic era has seen many advances in our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing's sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing's sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer.

01 Jan 2020·Nature Chemical BiologyQ1 · BIOLOGY

Processing for destruction

Q1 · BIOLOGY

Article

Author: Erb, Michael A

Phenotypic screening is an engine of discovery for bioactive small mols. and can unravel novel mechanisms and pathways controlling cellular physiol.A recent study reveals the CPSF complex as a pharmacol. tractable target of JTE-607 and context-specific cancer dependency.

100 Deals associated with JTE-607

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Indication	Highest Phase	Country/Location	Organization	Date
Systemic Inflammatory Response Syndrome	Phase 2	JP	Japan Tobacco, Inc.	-
Systemic Inflammatory Response Syndrome	Phase 2	-	Japan Tobacco (Hong Kong) Ltd.	-

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