6M8Q

Cleavage and Polyadenylation Specificity Factor Subunit 3 (CPSF3) in complex with NVP-LTM531

Summary for 6M8Q

• Entry DOI: 10.2210/pdb6m8q/pdb
• Descriptor: Cleavage and polyadenylation specificity factor subunit 3, ZINC ION, N-{3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzene-1-carbonyl}-L-phenylalanine, ... (5 entities in total)
• Functional Keywords: polyadenylation, metallo-b-lactamase, pre-mrna processing, artemis, v(d)j recombination, double-strand break repair, hydrolase, rna binding protein, hydroxylase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 110225.46

Authors

Weihofen, W.A.,Salcius, M.,Michaud, G. (deposition date: 2018-08-22, release date: 2019-11-27, Last modification date: 2023-10-11)

Primary citation

Ross, N.T.,Lohmann, F.,Carbonneau, S.,Fazal, A.,Weihofen, W.A.,Gleim, S.,Salcius, M.,Sigoillot, F.,Henault, M.,Carl, S.H.,Rodriguez-Molina, J.B.,Miller, H.R.,Brittain, S.M.,Murphy, J.,Zambrowski, M.,Boynton, G.,Wang, Y.,Chen, A.,Molind, G.J.,Wilbertz, J.H.,Artus-Revel, C.G.,Jia, M.,Akinjiyan, F.A.,Turner, J.,Knehr, J.,Carbone, W.,Schuierer, S.,Reece-Hoyes, J.S.,Xie, K.,Saran, C.,Williams, E.T.,Roma, G.,Spencer, M.,Jenkins, J.,George, E.L.,Thomas, J.R.,Michaud, G.,Schirle, M.,Tallarico, J.,Passmore, L.A.,Chao, J.A.,Beckwith, R.E.J.
CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.
Nat.Chem.Biol., 16:50-59, 2020

PubMed Abstract: 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.

PubMed: 31819276
DOI: 10.1038/s41589-019-0424-1

Experimental method

X-RAY DIFFRACTION (2.49 Å)