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Development of Acridone Derivatives: Targeting c-MYC Transcription in Triple-Negative Breast Cancer with Inhibitory Potential.

ABSTRACT: Breast cancer, especially the aggressive triple-negative subtype, poses a serious health threat to women. Unfortunately, effective targets are lacking, leading to a grim prognosis. Research highlights the crucial role of c-MYC overexpression in this form of cancer. Current inhibitors targeting c-MYC focus on stabilizing its G-quadruplex (G4) structure in the promoter region. They can inhibit the expression of c-MYC, which is highly expressed in triple-negative breast cancer (TNBC), and then regulate the apoptosis of breast cancer cells induced by intracellular ROS. However, the clinical prospects for the application of such inhibitors are not promising. In this research, we designed and synthesized 29 acridone derivatives. These compounds were assessed for their impact on intracellular ROS levels and cell activity, followed by comprehensive QSAR analysis and molecular docking. Compound N8 stood out, significantly increasing ROS levels and demonstrating potent anti-tumor activity in the TNBC cell line, with excellent selectivity shown in the docking results. This study suggests that acridone derivatives could stabilize the c-MYC G4 structure. Among these compounds, the small molecule N8 shows promising effects and deserves further investigation.

SUBMITTER: Liang JW

PROVIDER: S-EPMC10812579 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Development of Acridone Derivatives: Targeting c-MYC Transcription in Triple-Negative Breast Cancer with Inhibitory Potential.

Liang Jing-Wei JW Gao Zhi-Chao ZC Yang Lu-Lu LL Zhang Wei W Chen Ming-Zhe MZ Meng Fan-Hao FH

Antioxidants (Basel, Switzerland) 20231220 1

Breast cancer, especially the aggressive triple-negative subtype, poses a serious health threat to women. Unfortunately, effective targets are lacking, leading to a grim prognosis. Research highlights the crucial role of c-MYC overexpression in this form of cancer. Current inhibitors targeting c-MYC focus on stabilizing its G-quadruplex (G4) structure in the promoter region. They can inhibit the expression of c-MYC, which is highly expressed in triple-negative breast cancer ...[more]

PMID: 38275631

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Project description:Breast cancer (BC) is the most common cancer globally, accounting for 685,000 deaths in 2020. Triple-negative breast cancers (TNBC) lack oestrogen (ER) and progesterone (PR) hormone receptor expression and HER2 overexpression. TNBC represent 10-15% of all BC with high incidence in women under 50-years old that have BRCA mutations, and have a dismal prognosis. African American and Hispanic women are at higher risk partly due to the common occurrence of BRCA mutations. The standard treatment for TNBC includes surgery, radiotherapy, and chemotherapy although, resistance to all standard-of-care therapies eventually develops. It is crucial to identify and develop more efficacious therapeutics with different mechanisms of action to improve on survival in these women. Recent findings with oncolytic adenoviruses (OAds) may generate a new strategy to improve on the outcomes for women afflicted by TNBC and other types of BC. OAds are genetically engineered to selectively lyse, eliminate and recruit the host antitumour immune responses, leaving normal cells unharmed. The most common modifications are deletions in the early gene products including the E1B55 KDa protein, specific regions of the E1A protein, or insertion of tumour-specific promoters. Clinical trials using OAds for various adenocarcinomas have not yet been sufficiently evaluated in BC patients. Preclinical studies demonstrated efficacy in BC cell lines, including TNBC cells, with promising novel adenoviral mutants. Here we review the results reported for the most promising OAds in preclinical studies and clinical trials administered alone and in combination with current standard of care or with novel therapeutics. Combinations of OAds with small molecule drugs targeting the epidermal growth factor receptor (EGFR), androgen receptor (AR), and DNA damage repair by the novel PARP inhibitors are currently under investigation with reported enhanced efficacy. The combination of the PARP-inhibitor Olaparib with OAds showed an impressive anti-tumour effect. The most promising findings to date are with OAds in combination with antibodies towards the immune checkpoints or expression of cytokines from the viral backbone. Although safety and efficacy have been demonstrated in numerous clinical trials and preclinical studies with cancer-selective OAds, further developments are needed to eliminate metastatic lesions, increase immune activation and intratumoural viral spread. We discuss shortcomings of the OAds and potential solutions for improving on patient outcomes.

Dataset Information

Development of Acridone Derivatives: Targeting c-MYC Transcription in Triple-Negative Breast Cancer with Inhibitory Potential.

Publications

Development of Acridone Derivatives: Targeting <i>c-MYC</i> Transcription in Triple-Negative Breast Cancer with Inhibitory Potential.

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