Breast cancer, the so-called pink killer, is one of the major causes of death in women worldwide [1]. With a continuously increasing incidence rate year by year, BC has become the most common cancer in women globally, and around 13% of women (1 in 8) will be diagnosed during their lifetime [[2], [3], [4]]. Despite the enormous advances in cancer treatment in recent decades and the development of numerous synthetic drugs to target BC specifically, the survival rate for BC patients is still critical [5]. So far, the commonly known BC chemotherapeutics, regardless of their differential degrees of efficacy, have extensively shown unwholesome side effects and drug resistance [6,7]. Therefore, it is crucial to look for novel agents that can target cancer cells and their alternative survival pathways, as well as having minimal collateral damage on normal cells, to introduce safe and efficacious BC treatment solutions.

In several attempts to develop targeted anticancer agents, the protein kinase family of enzymes has been considered a target of interest. Being important regulators of the signal transduction pathways, protein kinases control various cellular functions, such as cell proliferation, differentiation, migration, and metabolism as well as the cell cycle phases [8]. One important family of the serine/threonine protein kinases is the family of Aurora kinase. The Aurora kinase enzymes are key regulators of mitosis, for proper and equal division of genomic material from parent to daughter cells [9]. They participate in many functions related to cell division, including centrosome duplication, mitotic spindle formation, alignment of metaphase chromosomes, mitotic checkpoint activation, and cytokinesis [10,11]. Errors in these processes or overexpression of such enzymes eventually lead to genetic instability and aneuploidy, which may result in tumorigenesis [12].

Aurora B kinase, which is also known as Aurora-1 or chromosomal passenger protein, is overexpressed in a variety of human cancers including BC [12,13]. Therefore, there is a great interest in developing Aurora B kinase inhibitors as targeted anticancer agents for BC treatment. Recently, a growing number of Aurora kinase inhibitors are being developed, and many of them are in phase I and II clinical trials [14]. However, only a few inhibitors have shown some level of selectivity towards one Aurora kinase subtype. To date, most discovered inhibitors exhibit selectivity towards Aurora A kinase, and much fewer ones towards Aurora B kinase [15]. Examples of non-selective Aurora kinase inhibitors include tozasertib (VX-680) [16] and ZM447439 [17], while selective Aurora B kinase inhibitors include hesperadin [18] and barasertib [19] (Fig. 1).

Beside the overexpression of Aurora B kinase in BC, there are other metabolic abnormalities that also affect carcinogenesis and tumor progression [24]. Under the combined consequences of genetic instability, inappropriate enzymes expression, signaling pathways impairment, and uncontrolled cell division, the cancer cells can exhibit significant metabolic shifting to satisfy their high energy demand [25]. This unique metabolic alteration is called the metabolic reprogramming of energy pathways [26].

In normal cells, energy is predominantly produced through the tricarboxylic acid cycle, also known as TCA or Krebs cycle, and mitochondrial oxidative phosphorylation (OXPHOS). On the other hand, under the effect of stress stimuli and nutrient-deprived conditions, cancer cells can exhibit a partial shift from OXPHOS to aerobic glycolysis to meet their energy needs, in a metabolic process known as the Warburg effect (Fig. 2) [27,28]. Despite the fact that aerobic glycolysis produces only two molecules of ATP per one glucose molecule, cancer cells can overcome this limit by increasing the cellular glucose uptake through overexpression of glucose transporters [29]. One other role of this metabolic reprogramming is the production of reactive oxygen species (ROS), such as hydrogen peroxide, superoxide anion, and hydroxyl radical, resulting in oxidative stress and ROS-induced DNA damage important for tumor development and prevalence [30,31]. The major source of intracellular ROS is the electron transport chain (ETC) [32], which is a component of the OXPHOS system consisting of a series of four protein complexes, complex I, II, III, and IV, found in the inner mitochondrial membrane [33]. Electrons are passed from one complex to another in a series of redox reactions ultimately leading to ATP and ROS production [34]. Whilst the Warburg effect is considered the main pathway for ATP production in cancer cells, in many tumor types, it is evidently noticeable that OXPHOS plays a critical role in delivering the bioenergetic and macromolecular anabolic requirements of proliferating cells essential for their progression and invasion [29]. Therefore, OXPHOS impairment can induce energy stress in cancer cells and augment the efficacy of targeted therapy [35,36]. Notably, BC exhibits distinct metabolic profiles with some BC cells having glycolytic phenotype and other BC cells being dependent on mitochondrial OXPHOS [[36], [37], [38]].

These unique metabolic features are now being exploited to repurpose a number of drugs that can interfere with mitochondrial metabolic reprogramming for cancer treatment [35], such as metformin [39] ivermectin [40], and fenofibrate [41], along with novel small molecules designed specifically to target OXPHOS and ETC [42,43]. Consequently, considering the dependence of cancer cells on the mitochondrial metabolic reprogramming, designing small molecules that can interfere with the mitochondrial metabolism could be beneficial in reducing cellular bioenergetics, overcoming resistance to antitumor agents, and inducing cell death in BC cells [44,45].