Synthesis and clinical application of small-molecule inhibitors and PROTACs of anaplastic lymphoma kinase

Pharmacological interventions that specifically target protein products of oncogenes in tumors have surfaced as a propitious therapeutic approach. Among infrequent genetic alterations, rearrangements of the anaplastic lymphoma kinase (ALK) gene, typically involving a chromosome 2 inversion that culminates in a fusion with the echinoderm microtubule-associated protein like 4 (EML4), lead to anomalous expression and activation of ALK. The inhibition of autophosphorylation and subsequent blockade of signal transduction by ALK tyrosine kinase inhibitors (TKIs) has been observed to elicit anti-tumor effects. Currently, four generations of ALK-positive targeted drugs have been investigated, providing a promising outlook for patients. The aim of this review is to furnish a comprehensive survey of the synthesis and clinical application of prototypical small-molecule ALK inhibitors in both preclinical and clinical phases, offering guidance for further development of ALK inhibitors for cancer therapy.