Anticancer benzoxaboroles block pre-mRNA processing by directly inhibiting CPSF3.

Publication Type:

Journal Article


Cell Chem Biol, Volume 31, Issue 1, p.139-149.e14 (2024)


Antineoplastic Agents, Boron Compounds, Cell Line, Tumor, Cleavage And Polyadenylation Specificity Factor, Endonucleases, Humans, RNA Precursors, RNA Processing, Post-Transcriptional


<p>A novel class of benzoxaboroles was reported to induce cancer cell death but the mechanism was unknown. Using a forward genetics platform, we discovered mutations in cleavage and polyadenylation specific factor 3 (CPSF3) that reduce benzoxaborole binding and confer resistance. CPSF3 is the endonuclease responsible for pre-mRNA 3&#39;-end processing, which is also important for RNA polymerase II transcription termination. Benzoxaboroles inhibit this endonuclease activity of CPSF3 in&nbsp;vitro and also curb transcriptional termination in cells, which results in the downregulation of numerous constitutively expressed genes. Furthermore, we used X-ray crystallography to demonstrate that benzoxaboroles bind to the active site of CPSF3 in a manner distinct from the other known inhibitors of CPSF3. The benzoxaborole compound impeded the growth of cancer cell lines derived from different lineages. Our results suggest benzoxaboroles may represent a promising lead as CPSF3 inhibitors for clinical development.</p>

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