(CTN News) – The survival rate for ovarian cancer is not very high, as it is often diagnosed at a late stage. Surgery and systemic chemotherapy can help improve the survival rate, but only to a certain extent.
PARP inhibitors have been shown to be effective in treating a limited number of ovarian cancer patients. However, drug therapies targeting transcription may also be a potential point of attack for treating ovarian cancer, as it is often characterized by frequent copy number alterations and dysregulated gene expression.
In a joint effort with ZHUANG Guanglei’s team at Renji Hospital, Shanghai Jiao Tong University School of Medicine, TAN and his colleagues conducted a comprehensive study on the regulatory roles of the CPSF complex in ovarian cancer.
Their investigation revealed that ovarian cancer relies uniquely on the transcription termination machinery, with the endonuclease activity of CPSF3 being crucial.
Armed with these discoveries, the researchers set out to validate CPSF3 as a potential target for therapeutic intervention.
They embarked on a search for small molecule inhibitors that could effectively disrupt the enzymatic activity of CPSF3 both in cells and in vivo.
Dr. TAN and his colleagues hypothesized that the benzoxazole moiety found in certain antimicrobial and antitumor agents could interact with the catalytic zinc ions of CPSF3.
Building on this understanding, they successfully developed potent, selective, bioavailable, and well-tolerated CPSF3 inhibitors, such as HQY426.
These inhibitors, along with their analogs, demonstrated significant antiproliferative effects in different ovarian cancer cell lines and effectively suppressed tumor growth in vivo when used alone or in combination with cisplatin or PARP inhibitors.
In contrast, previously reported CPSF3 inhibitors showed minimal activity.
Additionally, introducing specific mutations in the catalytic site of CPSF3 rendered ovarian cancer cells resistant to HQY426 and its analogs, further confirming the targeted nature of these inhibitors.
To summarize, the identification of these inhibitors confirms the significance of CPSF3-dependent transcription termination in ovarian cancer and its potential for treatment.
Additionally, it presents a hopeful group of boron-containing compounds for the creation of targeted anticancer medications.