Recent advances in the discovery of anti-breast cancer agents based on dual-target inhibition strategies.

Abstract

Breast cancer is characterized by marked heterogeneity and redundant signaling networks, which leave single-target treatments susceptible to adaptive resistance. Traditional combination treatments are often limited by inconsistent pharmacokinetic profiles and cumulative systemic toxicity. In contrast, dual-target inhibitors enable concurrent regulation of two functionally related biological targets within a single molecular framework, effectively overcoming target-specific drug resistance and addressing the pharmacokinetic asynchrony characteristic of multi-drug regimens. Consequently, the design of dual-target drugs has become a prominent area of research in anticancer drug development. From a rational molecular design perspective, this review systematically summarizes advancements over the past five years (2020-2025) in the construction of dual-target anticancer agents using mainstream strategies, including pharmacophore fusion and scaffold hopping. Additionally, we highlight typical dual-target candidates involved in epigenetic remodeling, synthetic lethality coupled with DNA damage repair, synergistic inhibition of kinase pathways, and modulation of the tumor microenvironment, emphasizing their design principles, structure-activity relationships (SAR), and underlying pharmacological mechanisms. Overall, the perspectives presented herein aim to provide a theoretical framework to support the rational development of highly effective, low-toxicity anticancer agents with promising potential for clinical translation.