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The past, present, and future of ALK-targeted drug discovery

Hui Qu1, Jingru Zhang2, Xinxin Zhao3

  • 1Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China.

European Journal of Medicinal Chemistry
|August 13, 2025
PubMed

Insights

New anaplastic lymphoma kinase (ALK) inhibitors are being developed to treat cancers like lung cancer. This review focuses on recent advancements in ALK inhibitor medicinal chemistry and future directions for improved cancer therapies.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase crucial for nervous system development.
  • Aberrant ALK activation via genetic alterations drives cancers such as non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma (ALCL), and neuroblastoma.
  • ALK alterations contribute to cancer development, proliferation, and resistance to therapy.

Purpose of the Study:

  • To review the development of anaplastic lymphoma kinase (ALK) inhibitors from 2020 to the present.
  • To focus on medicinal chemistry optimization of ALK inhibitors.
  • To discuss emerging resistance mechanisms and future directions for ALK-targeted therapies.

Main Methods:

  • Literature review of recent advancements in ALK inhibitor development.
  • Analysis of medicinal chemistry strategies for optimizing ALK inhibitors.
  • Discussion of resistance mechanisms and clinical challenges.

Main Results:

  • Significant progress in developing second- and third-generation ALK inhibitors.
  • Optimization efforts focus on overcoming resistance mutations and enhancing central nervous system (CNS) penetration.
  • Identification of emerging resistance mechanisms and challenges in achieving durable responses.

Conclusions:

  • Next-generation ALK inhibitors aim for improved target specificity and reduced off-target effects.
  • Future research should focus on overcoming resistance and enhancing clinical outcomes in ALK-driven cancers.
  • This review provides a roadmap for developing more effective ALK-targeted therapies.
Keywords:
ALKDrug resistanceNSCLCTargeted therapyTyrosine kinase inhibitor

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