Anticancer benzoxaboroles block pre-mRNA processing by directly inhibiting CPSF3

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• A novel class of benzoxaboroles has demonstrated the ability to induce cancer cell death.
• The precise mechanism underlying benzoxaborole-induced cancer cell death remained unidentified.

Purpose of the Study:

• To elucidate the mechanism by which benzoxaboroles induce cancer cell death.
• To identify the molecular target of benzoxaboroles and their role in cancer biology.

Main Methods:

• Utilized a forward genetics platform to identify resistance mechanisms.
• Employed in vitro biochemical assays to assess enzyme inhibition.
• Conducted X-ray crystallography to determine the binding mode of benzoxaboroles to CPSF3.
• Evaluated the anti-cancer effects of benzoxaboroles on various cancer cell lines.

Main Results:

• Mutations in cleavage and polyadenylation specific factor 3 (CPSF3) were found to confer resistance to benzoxaboroles.
• Benzoxaboroles were shown to inhibit the endonuclease activity of CPSF3 in vitro.
• Inhibition of CPSF3 by benzoxaboroles curbed transcriptional termination in cells, leading to the downregulation of essential genes.
• X-ray crystallography revealed a unique binding interaction between benzoxaboroles and the active site of CPSF3.
• Benzoxaborole compounds effectively impeded the growth of diverse cancer cell lines.

Conclusions:

• Benzoxaboroles function by inhibiting the endonuclease activity of CPSF3, a key enzyme in pre-mRNA processing and transcription termination.
• The distinct binding mechanism of benzoxaboroles to CPSF3 offers a novel approach for drug development.
• Benzoxaboroles show significant potential as a new class of CPSF3 inhibitors for cancer therapy.