Abstract
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer which presents a high rate of relapse, metastasis, and mortality. Nowadays, the absence of approved specific targeted therapies to eradicate TNBC remains one of the main challenges in clinical practice. Drug discovery is a long and costly process that can be dramatically improved by drug repurposing, which identifies new uses for existing drugs, both approved and investigational. Drug repositioning benefits from improvements in computational methods related to chemoinformatics, genomics, and systems biology. To the best of our knowledge, we propose a novel and inclusive classification of those approaches whereby drug repurposing can be achieved in silico: structure-based, transcriptional signatures-based, biological networks-based, and data-mining-based drug repositioning. This review specially emphasizes the most relevant research, both at preclinical and clinical settings, aimed at repurposing pre-existing drugs to treat TNBC on the basis of molecular mechanisms and signaling pathways such as androgen receptor, adrenergic receptor, STAT3, nitric oxide synthase, or AXL. Finally, because of the ability and relevance of cancer stem cells (CSCs) to drive tumor aggressiveness and poor clinical outcome, we also focus on those molecules repurposed to specifically target this cell population to tackle recurrence and metastases associated with the progression of TNBC.
Highlights
Breast cancer is the second most common cancer and the second cause of cancer death among US women, after lung cancer [1]
Apart from molecular docking, the user can perform pharmacophore mapping, which consists of searching of ligands that can be matched to a pharmacophore, i.e., a set of molecular features such as hydrogen bonds, hydrophobic groups, or chemical substructures, that enable the recognition of a ligand by a receptor and their biological activity
Pharmacophore features can be derived from protein-binding site or protein–ligand complexes structures, and software packages such as Catalyst, Unity (Tripos, www.tripos.com), or PharmMapper can be used for pharmacophore searching [24,26]
Summary
Breast cancer is the second most common cancer and the second cause of cancer death among US women, after lung cancer [1]. TNBC is the breast cancer subtype with the poorest overall survival (OS) and the highest rates of metastases [5], most commonly in lungs and brain [6]. It is more frequent in women in younger ages and black race, presenting an incidence rate about twice as high compared with white race [1]. The process of creating and testing a new drug for TNBC is a cost- and time-consuming challenge that requires a huge investment and comprises high failure rates. Drug repurposing has been considered an increasingly successful approach for developing new therapies [7]
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