Researchers, led by Tan Li from the Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences, have made significant strides in identifying potential therapeutic avenues for ovarian cancer. They developed novel small molecule inhibitors targeting CPSF3, a critical component of the cleavage and polyadenylation specificity factor (CPSF) complex that plays a pivotal role in pre-mRNA splicing and transcription termination. Their findings, published in Science Advances on Nov. 22, offer promising prospects for treating ovarian cancer, a highly lethal gynecological cancer often diagnosed at advanced stages.
While surgery and systemic chemotherapy marginally enhance survival rates, targeted therapies using PARP inhibitors are effective in only a subset of patients. The researchers explored the regulatory functions of the CPSF complex in ovarian cancer, revealing the unique dependence of ovarian cancer on transcription termination machinery, particularly the indispensable endonuclease activity of CPSF3.
To validate CPSF3 as a potential therapeutic target, the team sought small molecule inhibitors capable of perturbing CPSF3's enzymatic activity both in cells and in vivo. Leveraging knowledge about benzoxaborole-containing antimicrobial and antitumor agents, they developed potent, selective, bioavailable, and tolerable CPSF3 inhibitors, including HQY426. These inhibitors demonstrated robust antiproliferative effects in various ovarian cancer cell lines and effectively suppressed tumor growth in vivo, either as standalone treatments or in combination with cisplatin or PARP inhibitors.
In contrast, previously reported CPSF3 inhibitors exhibited minimal activity. Notably, point mutations in key catalytic site residues of CPSF3 conferred resistance to HQY426 and its analogs in ovarian cancer cells, confirming the specificity of these targeted inhibitors.
In summary, the discovery of these inhibitors not only highlights CPSF3-dependent transcription termination as a crucial mechanism in ovarian cancer but also presents a promising class of boron-containing leads for developing targeted anticancer drugs. This research opens new avenues for therapeutic interventions in ovarian cancer, providing hope for improved treatment strategies against this formidable disease.
Source: Chinese Academy of Sciences