Chalcone Derivatives as Multitarget Modulators of Signalling Pathways in Breast Cancer: Mechanisms, Challenges, and Future Perspectives.

Abstract

Breast cancer continues to be one of the leading causes of morbidity and mortality for women all over the world, noted for its heterogeneity, metastasis, and resistance to conventional therapies. In this regard, chalcone derivatives, which are flavonoids found in nature or synthesized chemically, are emerging as promising anticancer agents due to their ability to modulate multiple oncogenic signaling pathways and their structural flexibility. The current review systematically evaluates chalcone derivatives with respect to modulation of apoptotic pathways, cell cycle arrest, inhibition of angiogenesis and metastasis, reversal of multidrug resistance, and disruption of pathways including PI3K/Akt/mTOR, MAPK/ERK, NF-κB, JAK/STAT, and Wnt/β-catenin. Structure- activity relationship insights are highlighted to explain how chemical modifications influence bioactivity and selectivity. Furthermore, this study discusses the translational barriers, including pharmacokinetic limitations, toxicity concerns, and the need for nanotechnology-based delivery systems. Current progress in hybrid design, computational modeling, and combination therapies underscores chalcones' potential as next-generation breast cancer therapeutics. Despite challenges in clinical translation, chalcone derivatives represent a versatile scaffold capable of overcoming therapeutic resistance and providing a foundation for precision oncology.