Structure-based design and pharmacological profiling of functionalized pyrazoles targeting lung cancer pathways

According to the latest cancer statistics from 2023, this disease remains a major global public health issue and represents the second leading cause of mortality after cardiovascular diseases. Studies indicate that lung and bronchial cancer remains the deadliest form for both men and women. Heterocyclic compounds, such as pyrazoles, exhibit remarkable pharmacological properties that confer significant potential in cancer treatment. The introduction of functional groups, such as an aromatic ring and a cyanoester, onto these molecules has emerged as a promising strategy in oncology, enhancing their efficacy and relevance as anticancer agents. This study focuses on the development of new substituted pyrazole-based molecules targeting lung cancer. The synthesized derivatives 3a-d were characterized by nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS). Network pharmacology (NP) analysis highlighted the interconnected roles of key therapeutic targets, such as AKT serine/threonine kinase 1 (AKT1), epidermal growth factor receptor (EGFR), and estrogen receptor 1 (ESR1), in cellular signaling pathways, particularly those related to oncogenesis and hypoxia. In silico studies, including molecular docking, were performed on the synthesized compounds against AKT1. These analyses revealed a favorable binding energy for compound 3a (Ethyl 3-(4-chlorophenyl)-2-cyano-3-(3-hydroxy-5-methyl-1H-pyrazol-4-yl)propanoate) (-6.92 kcal/mol), which is comparable to that of Capivasertib (-7.46 kcal/mol). Furthermore, molecular dynamics simulations confirmed the remarkable stability of the 3a-AKT1 complex. This work represents a significant step toward the design of novel, effective anticancer agents.