Potential small-molecule tyrosine kinase inhibitors (TKIs) for the treatment of triple-negative breast cancer (TNBC): Targets, structure-activity relationships, and clinical studies.

Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), leading to limited clinical treatment options and a poor prognosis. Currently, conventional chemotherapy remains the mainstay of treatment for TNBC patients, but its efficacy is hindered by limited clinical benefits and profound adverse effects, making the search for more effective therapeutic strategies a matter of urgency. Recently, small-molecule inhibitors have achieved significant breakthroughs in TNBC research. Specifically, the abnormal activation of tyrosine kinase (TK) signaling pathways serves as a critical driver of TNBC progression, positioning small-molecule tyrosine kinase inhibitors (TKIs) as a major research hotspot. Therefore, this review systemically delineates the pathogenesis and treatment modalities of TNBC, focusing on the TKIs evaluated in recent clinical trials either as monotherapies or in combination with other therapeutics, such as chemotherapeutic agents, immunotherapies, and antibody-drug conjugates (ADCs). Furthermore, newly developed small-molecule inhibitors are summarized, outlining their enzyme inhibitory activities, anti-tumor activities, and structure-activity relationships (SAR). The involved tyrosine kinase targets encompass VEGFR, EGFR, FGFR, AXL, ACK1, and MET. Given the challenges in TNBC drug development due to the absence of well-defined biomarkers, this comprehensive summary of the latest advances in targeted therapies aims to provide a valuable reference for the future development of individualized and precision treatments for TNBC patients.