Novel BH4-BCL-2 Domain Antagonists Induce BCL-2-Mediated Apoptosis in Triple-Negative Breast Cancer

Abstract

Targeting the challenging tumors lacking explicit markers and predictors for chemosensitivity is one of the major impediments of the current cancer armamentarium. Triple-negative breast cancer (TNBC) is an aggressive and challenging molecular subtype of breast cancer, which needs astute strategies to achieve clinical success. The pro-survival B-cell lymphoma 2 (BCL-2) overexpression reported in TNBC plays a central role in deterring apoptosis and is a promising target. Here, we propose three novel BH4 mimetic small molecules, SM396, a covalent binder, and two non-covalent binders, i.e., SM216 and SM949, which show high binding affinity (nM) and selectivity, designed by remodeling the existing BCL-2 chemical space. Our mechanistic studies validate the selectivity of the compounds towards cancerous cells and not on normal cells. A series of functional assays illustrated BCL-2-mediated apoptosis in the tumor cells as a potent anti-cancerous mechanism. Moreover, the compounds exhibited efficacious in vivo activity as single agents in the MDA-MB-231 xenograft model (at nanomolar dosage). Overall, these findings depict SM216, SM396, and SM949 as promising leads, pointing to the clinical translation of these compounds in targeting triple-negative breast cancer.

Predictive value of multimodal ultrasound imaging and BCL-2 expression levels in the outcome of neoadjuvant chemotherapy for breast cancer

“…Previous studies have established a connection between greater tissue hardness in infiltrating lesions within breast masses and an elevated risk of poor patient prognosis [25]. NAC can induce changes in both the internal and surrounding tissues of breast cancer lesions due to the effects of the drugs, leading to alterations in tissue hardness [26]. In our present study, we observed significant changes in the ultrasound elastography parameter SR before and after treatment, while only the group of patients achieving pCR had decreased elastic scores after NAC treatment.…”