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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
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Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK)

Xiaotian Kong1,2, Peichen Pan1, Huiyong Sun1

  • 1Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , Zhejiang 310058 , China.

Journal of Medicinal Chemistry
|August 17, 2019
PubMed

Insights

Anaplastic lymphoma kinase (ALK) is crucial in cancers like NSCLC. This review covers ALK inhibitors, including FDA-approved drugs and novel PROTACs, to combat resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase implicated in various cancers, notably non-small cell lung cancer (NSCLC), anaplastic large cell lymphoma (ALCL), and neuroblastomas.
  • The insulin receptor (IR) subfamily includes ALK, highlighting its significance in cellular signaling pathways relevant to cancer development.

Purpose of the Study:

  • To provide a comprehensive overview of anaplastic lymphoma kinase (ALK) inhibitors.
  • To detail the discovery and development of drugs targeting ALK, focusing on chemotypes, efficacy, selectivity, and resistance mechanisms.
  • To explore emerging therapeutic strategies, including proteolysis targeting chimeras (PROTACs), for overcoming drug resistance in ALK-driven cancers.

Main Methods:

  • Literature review of ALK inhibitors, including small-molecule drugs and proteolysis targeting chimeras (PROTACs).
  • Analysis of ALK inhibitor chemotypes, pharmacological activity, kinase selectivity, and mechanisms of acquired resistance.
  • Examination of current and potential therapeutic strategies to address resistance to ALK-targeted therapies.

Main Results:

  • Five small-molecule ALK inhibitors (Crizotinib, Ceritinib, Alectinib, Brigatinib, Lorlatinib) are FDA-approved for ALK-positive NSCLC.
  • Novel type-I 1/2 and type-II ALK inhibitors demonstrate improved kinase selectivity and enhanced efficacy against resistant mutations.
  • Proteolysis targeting chimera (PROTAC) technology has been successfully applied to develop ALK degraders, offering a new therapeutic modality.

Conclusions:

  • Targeted therapies against ALK have significantly advanced cancer treatment, particularly for ALK-positive NSCLC.
  • Ongoing research into novel inhibitors and degraders is crucial for overcoming therapeutic resistance and improving patient outcomes.
  • The development of PROTACs represents a promising new avenue for effectively targeting and eliminating ALK in cancer therapy.

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