Current landscape and recent developments of PI3K/AKT/mTOR targeted inhibitors for breast carcinoma

Breast cancer continues to be among the primary contributors of malignancy-related mortality and morbidity in women globally. The PI3K/AKT/mTOR (PAM) pathway regulates cell proliferation, survival, metabolism, and treatment resistance. The over activation of this pathway appears prevalent across multiple breast carcinoma subtypes. As a consequence, substantial research has concentrated on developing small-molecule inhibitors that are capable of regulating abnormal PAM signalling and enhancing therapeutic effects. In this review, we aimed to outline the developments in the area of PAM blockers targeting breast cancer. In an effort against cancer, small-molecule antagonists with dysregulated signalling pathways have been studied extensively. The PAM pathway was often disrupted during breast carcinoma. The presented heterocyclic compounds can be divided into numerous categories based on their chemical core and substituents: triazines, quinazolines, quinolines, pyrimidines, benzimidazoles, thiazolidines, coumarins, pyridazines, thiazoles, triazoles, imidazo-naphthyridines, and pyridines. Our investigation focused on their synthesis, structure-activity relationship (SAR) analysis, and inhibitory effect against PAM signalling. Quinazolin-tyrphostin, Oxazolo-Pyrimidine, and Thiazole derivatives effectively inhibit PI3K with IC₅₀ values of 0.008 μM, 0.046 to 0.12 μM, and 13 nM, respectively. In addition, Quinoline/Chalcone Hybrids inhibited PI3K at 52 nM due to the presence of hydrogen bonding and hydrophobic interactions. These compounds revealed dual or multitargeted inhibition, bypassing resistance mechanisms and enhancing therapeutic properties. Molecular docking and SAR investigations offered helpful insight into the binding mechanisms of inhibitors within the active sites of PI3K, AKT, and mTOR, as well as a structural foundation for further optimization. Overall, heterocyclic-based scaffolds have shown promising results for developing safer and more selective breast cancer therapies.