Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors
Pierre-Yves Michellys1, Bei Chen1, Tao Jiang1
1Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 920121, United States.
Abstract:
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described.
Insights
Researchers discovered new anaplastic lymphoma kinase (ALK) inhibitors by modifying existing compounds. These novel inhibitors show promise for treating ALK-driven cancers like anaplastic large cell lymphoma.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase implicated in various cancers.
- Genetic alterations in ALK, such as fusions (NPM-ALK, EML4-ALK) or activating mutations, drive oncogenesis.
- ALK dysregulation is observed in anaplastic large cell lymphoma (ALCL) and neuroblastoma.
Purpose of the Study:
- To discover novel and selective anaplastic lymphoma kinase (ALK) inhibitors.
- To explore modifications of the 2,4-diaminopyridine core for enhanced inhibitory activity.
- To evaluate the therapeutic potential of these new inhibitors in preclinical models.
Main Methods:
- Chemical synthesis of novel 2,4-diaminopyridine derivatives.
- Structure-activity relationship (SAR) studies to optimize inhibitor potency and selectivity.
- Pharmacokinetic profiling, including absorption, distribution, metabolism, and excretion (ADME).
- In vivo efficacy testing in a mouse xenograft model of anaplastic large cell lymphoma (ALCL).
Main Results:
- Identification of novel, selective inhibitors targeting the anaplastic lymphoma kinase (ALK).
- Detailed structure-activity relationship (SAR) data guiding inhibitor design.
- Favorable absorption, distribution, metabolism, and excretion (ADME) properties observed.
- Demonstrated in vivo efficacy of the novel inhibitors in an anaplastic large cell lymphoma (ALCL) xenograft model.
Conclusions:
- Novel 2,4-diaminopyridine-based compounds effectively inhibit anaplastic lymphoma kinase (ALK).
- These inhibitors exhibit promising preclinical efficacy and pharmacokinetic profiles.
- The findings support the development of these compounds as potential therapeutics for ALK-driven malignancies.
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