In silico, synthesis, and in vitro studies of novel FOXM1 Inhibitors for targeted triple negative breast cancer therapy

Title : In silico, synthesis, and in vitro studies of novel FOXM1 Inhibitors for targeted triple negative breast cancer therapy

Abstract:

Triple-negative breast cancer (TNBC) is subtype of breast cancer is known for aggressive, leading to early relapses, metastasis and poor clinical prognosis. Significant heterogeneity and drug resistant phenotype and lack of effective targeted therapeutics contribute to poor patient survival. Forkhead box (FOX) protein M1 (FOXM1), a proto-oncogenic transcription factor, is overexpresses in TNBC cells and drives cell proliferation invasion and tumorigenesis. We have previously found that FOXM1 expression is a poor prognostic factor and associated with shorter patient survival in TNBC patients. Using genetic methods, we for the first time validated FOXM1 as a molecular target in TNBC. The inhibition of FOXM1 significantly suppresses the growth of TNBC tumour xenografts in mice by regulating the eEF2K signalling pathway. Currently, there is no FDA-approved FOXM1 inhibitor for clinical translation as existing inhibitors are not potent or selective for FOXM1 inhibition. Therefore, identification of novel, safe, selective and potent inhibitors are needed to effectively target FOXM1 TNBC tumours. In current study, we designed and synthesized novel potential FOXM1 inhibitors by using in silico studies such as molecular docking, molecular dynamics (MD) simulations, and ADMET predictions. The newly synthesized compounds were evaluated in vitro in TNBC cells lines by performing cell proliferation and colony formation assays, and western blot analysis for FOXM1 inhibition. Synthesized some thiazole-containing compounds were found to be highly active and inhibited cell proliferation and inhibited FOXM1 in TNBC cells. These promising results will be discussed.

Audience Take Away Notes:

• This study may be possible to identify effective FOXM1 inhibitors for the treatment of Triple Negative Breast Cancer
• In the field of health/pharmaceuticals, which is among the priority areas, our FOXM1 inhibitor/drug development studies for the treatment of breast cancer can contribute to cancer treatment, as well as to the quality of life by solving the disease and increasing the number of healthy individuals
• Within this study, we want to carry out to solve these problems is related to this type of impact and development plan

Biography:

Dr. Comert Onder received her PhD degree in Organic Chemistry at the Canakkale Onsekiz Mart University, Turkey in 2019. She joined the research group of Prof. Dr. Ozpolat at MD Anderson Cancer Center, Houston, TX, USA in 2018. She has been studying as an Assistant Professor at the Faculty of Medicine Çanakkale Onsekiz Mart University since 2020. There are several published research articles, congress presentations, book chapters, and patent applications. Her research areas are drug design, discovery and development, medicinal chemistry, cancer biology, organic chemistry, and natural products.