Rational design of dual ALK inhibitors: scaffolds and strategies to circumvent drug resistance.

Anaplastic lymphoma kinase (ALK) is a clinically validated oncogenic driver in multiple malignancies; however, the long-term efficacy of ALK tyrosine kinase inhibitors is frequently compromised by tumor heterogeneity, adaptive signaling, and compensatory pathway activation. Although successive generations of ALK inhibitors have addressed several resistance mutations, achieving durable therapeutic responses remains challenging. In this context, dual-target ALK inhibitors-single molecular entities capable of concurrently inhibiting ALK and complementary oncogenic targets-have emerged as a rational polypharmacological strategy. This review summarizes recent advances (2018-2025) in the rational design of dual ALK inhibitors, highlighting key chemotypes including 2,4-diaminopyrimidines, 2-aminopyridines, and pyrazolo[1,5-a]pyrimidines. Structure-based drug design strategies such as pharmacophore hybridization, scaffold hopping, solvent-front mutation engineering, and macrocyclization are critically analyzed with respect to potency, selectivity, CNS penetration, and resistance coverage. Dual-target combinations involving ALK with TRK, EGFR, ROS1, HDAC, CDK4/6, FAK, and related targets are systematically discussed, supported by SAR trends, crystallographic insights, and molecular modeling. Collectively, this review provides a design-focused framework to guide the development of next-generation dual ALK inhibitors aimed at achieving durable pathway suppression in ALK-driven cancers. Solvent-front mutation engineering.