Design and Development of New Generation ALK Inhibitors Driven by Structure–Activity Relationship Studies of 2,4-Diarylaminopyrimidine Derivatives

Due to the oncogenic role of anaplastic lymphoma kinase (ALK) in various malignancies, particularly in non-small cell lung cancer (NSCLC), lymphoma, and neuroblastoma, mutations or rearrangements of ALK frequently drive tumorigenesis and progression. Consequently, the development of new-generation ALK inhibitors, particularly therapeutic strategies targeting ALK resistance mutations, has emerged as a critical focus in cancer drug research and development. This study established a robust Topomer CoMFA model, validated through both internal and external assessments, Y-randomization testing, and validation with the extreme learning machine (ELM) model, to systematically analyze the structure–activity relationships (SAR) of a series of 52 derivatives, specifically designed as 2,4-diarylaminopyrimidines, which exhibit significant inhibitory activity. Based on the optimal model, 24 novel compounds demonstrating ideal inhibitory activity were successfully designed, with three potential lead compounds identified through molecular docking. Subsequent investigations utilized DFT calculations, molecular dynamics simulations, principal component analysis, and binding free energy calculations to elucidate the binding modes and mechanisms of these compounds. Furthermore, ADMET predictions indicated promising pharmacological potential for these compounds. These results offer substantial theoretical support for the targeted treatment of ALK-related tumors, while also laying the groundwork for future investigations into novel ALK inhibitors.