Selectively targeting BCL6 using a small molecule inhibitor is a potential therapeutic strategy for ovarian cancer.

Ovarian cancer is one of the tumors with the highest fatality rate among gynecological tumors. The current 5-year survival rate of ovarian cancer is <35%. Therefore, more novel alternative strategies and drugs are needed to treat ovarian cancer. The transcription factor B-cell lymphoma 6 (BCL6) is critically associated with poor prognosis and cisplatin resistance in ovarian cancer treatment. Therefore, BCL6 may be an attractive therapeutic target for ovarian cancer. However, the role of targeting BCL6 in ovarian cancer remains elusive. Here, we developed a novel BCL6 small molecule inhibitor, WK369, which exhibits excellent anti-ovarian cancer bioactivity, induces cell cycle arrest and causes apoptosis. WK369 effectively inhibits the growth and metastasis of ovarian cancer without obvious toxicity in vitro and in vivo. meanwhile, WK369 can prolong the survival of ovarian cancer-bearing mice. It is worth noting that WK369 also has significant anti-tumor effects on cisplatin-resistant ovarian cancer cell lines. Mechanistic studies have shown that WK369 can directly bind to the BCL6-BTB domain and block the interaction between BCL6 and SMRT, leading to the reactivation of p53, ATR and CDKN1A. BCL6-AKT, BCL6-MEK/ERK crosstalk is suppressed. As a first attempt, our study demonstrates that targeting BCL6 may be an effective approach to treat ovarian cancer and that WK369 has the potential to be used as a candidate therapeutic agent for ovarian cancer.

A small molecule BCL6 inhibitor as chemosensitizers in acute myeloid leukemia.

BCL6 is a transcriptional repressor that regulates multiple genes involved in immune cell differentiation, DNA damage repair, cell cycle, and apoptosis, and is a carcinogenic factor in acute myeloid leukemia (AML). AML is one of the four major types of leukemia with the 5-year survival rate of patients is less than 20% and chemotherapy resistance remains the major obstacle to the treatment failure of AML. We identified WK499, a small molecule compound that can bind to BCL6BTB structure. Treatment with WK499 hinders the interactions between BCL6 with its corepressor proteins, resulting in a remarkable change of BCL6 downstream genes and anti-proliferative effects in AML cells, and inducing cell cycle arrest and apoptosis. We verified that AraC and DOXo could induce BCL6 expression in AML cells, and found that WK499 had a synergistic effect when combined with chemotherapeutic drugs. We further proved that WK499 and AraC could achieve a better result of inhibiting the growth of AML in vivo. These findings indicate that WK499, a small molecule inhibitor of BCL6, not only inhibits the proliferation of AML, but also provides an effective therapeutic strategy for increasing AML sensitivity to chemotherapy.

Combined treatment of disulfiram with PARP inhibitors suppresses ovarian cancer.

Introduction: Due to the difficulty of early diagnosis, nearly 70% of ovarian cancer patients are first diagnosed at an advanced stage. Thus, improving current treatment strategies is of great significance for ovarian cancer patients. Fast-developing poly (ADP-ribose) polymerases inhibitors (PARPis) have been beneficial in the treatment of ovarian cancer at different stages of the disease, but PARPis have serious side effects and can result in drug resistance. Using PARPis in combination with other drug therapies could improve the efficacy of PRAPis.In this study, we identified Disulfiram as a potential therapeutic candidate through drug screening and tested its use in combination with PARPis. Methods: Cytotoxicity tests and colony formation experiments showed that the combination of Disulfiram and PARPis decreased the viability of ovarian cancer cells. Results: The combination of PARPis with Disulfiram also significantly increased the expression of DNA damage index gH2AX and induced more PARP cleavage. In addition, Disulfiram inhibited the expression of genes associated with the DNA damage repair pathway, indicating that Disulfiram functions through the DNA repair pathway. Discussion: Based on these findings, we propose that Disulfiram reinforces PARPis activity in ovarian cancer cells by improving drug sensitivity. The combined use of Disulfiram and PARPis provides a novel treatment strategy for patients with ovarian cancer.