Novel Chalcone Derivatives as Potent Lyn Tyrosine Kinase Inhibitors: A Promising In Silico Approach for Targeted Therapy in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) accounts for approximately 10–15% of breast cancer cases and poses a significant clinical challenge due to its aggressive nature and poorer survival outcomes compared to other subtypes. This is primarily attributed to the lack of estrogen, progesterone, and HER2 receptors, which renders conventional hormone-based therapies ineffective. In this study, we employed in silico approaches to design and evaluate novel chalcone derivatives as potential inhibitors of Lyn tyrosine kinase, a critical enzyme implicated in TNBC progression. The designed compounds were screened for drug-likeness and toxicity, all meeting Lipinski’s rule of five and demonstrating favorable toxicity profiles. Molecular docking studies and post dock analysis identified five promising ligands; CHCN1, CHCN19, CHCN48, CHCN333, and CHCN94 that exhibited strong binding affinities to key active site residues of Lyn kinase, including Asp385, Phe386, Gly387, Lys275, and Glu290. Among these, CHCN1 showed the highest binding affinity at –8.4 kcal/mol, likely due to interactions with Asp385 and Lys275. These results suggest that the chalcone derivatives may effectively disrupt Lyn-mediated signaling pathways essential for cancer cell survival, potentially inhibiting proliferation, metastasis, and invasion. Overall, this study provides valuable insights into the therapeutic potential of chalcone derivatives for Triple Negative Breast Cancer, offering promising avenues for targeted intervention.