https://www.scienceopen.com/hosted-document?doi=10.15212/AMM-2024-0070
Announcing a new publication for Acta Materia Medica journal. Kinases have a pivotal role in phosphorylation and kinase dysregulation has been implicated in the occurrence and progression of various diseases. By mid-2024 the Food and Drug Administration had approved 81 small-molecule kinase inhibitors targeting greater than 30 kinases, providing substantial clinical benefits for patients with cancer and other diseases. However, many reported kinase inhibitors exhibit poor target selectivity, limited solubility, and issues with drug resistance.
To address these challenges medicinal chemists have used a macrocyclization strategy to optimize these molecules and three macrocyclic kinase inhibitors (lorlatinib [ALK/ROS1], pacritinib [Flt3/JAK2], and repotrectinib [TRK/ROS1]) have received FDA approval. The macrocyclization strategy is now widely used to enhance kinase inhibitory activity, overcome drug resistance caused by point mutations, improve kinase selectivity, and optimize drug-like properties.
In this review the authors comprehensively review the utilization of macrocyclization in the optimization of kinase inhibitors by detailing the structural modification process from lead compounds to macrocyclic molecules that has been applied in recent years. In addition, the limitations of existing macrocyclic kinase inhibitors are discussed and key considerations for the development of improved macrocyclic molecules are proposed. This review offers valuable insights for future advances in kinase inhibitor development.
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eISSN 2737-7946
Kun Xing, Shujun Li and Jinghuan Li et al. Application of a macrocyclization strategy in kinase inhibitor development. Acta Materia Medica. 2025. Vol. 3(4):521-555. DOI: 10.15212/AMM-2024-0070
Acta Materia Medica