以针对肿瘤中癌基因蛋白产物的药物干预作为治疗策略已被证明是一种有前途的方法。在罕见的遗传变异中，缺陷性淋巴瘤激酶（ALK）基因的重排，通常涉及一个2号染色体的倒位，导致与地中海生物的微管相关蛋白4（EML4）融合，从而引起ALK的异常表达和激活。已观察到ALK酪氨酸激酶抑制剂（TKI）抑制自身磷酸化和信号转导，并产生抗肿瘤效应。目前，已研究了四代ALK阳性靶向药物，为患者提供了有希望的前景。本文的目的是提供对原型小分子ALK抑制剂在临床前和临床阶段合成和临床应用的全面调查，为进一步发展ALK抑制剂用于癌症治疗提供指导。Copyright © 2023 Elsevier Inc. All rights reserved.

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.Copyright © 2023 Elsevier Inc. All rights reserved.