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.

Automated summary

Rearrangements of the ALK gene in tumors lead to abnormal expression and activation, which can be inhibited by ALK tyrosine kinase inhibitors (TKIs) to elicit anti-tumor effects. Four generations of ALK-positive targeted drugs have been investigated, providing a promising outlook for patients.