Kinase inhibitor macrocycles: a perspective on limiting conformational flexibility when targeting the kinome with
Baku Acharya1, Debasmita Saha1,2, Daniel Armstrong1
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA BAFrett@uams.edu.
Abstract:
Methods utilized for drug discovery and development within the kinome have rapidly evolved since the approval of imatinib, the first small molecule kinase inhibitor. Macrocycles have received increasing interest as a technique to improve kinase inhibitor drug properties evident by the FDA approvals of lorlatinib, pacritinib, and repotrectinib. Compared to their acyclic counterparts, macrocycles can possess improved pharmacodynamic and pharmacokinetic properties. This review highlights clinical success stories when implementing macrocycles in kinase-based drug discovery and showcases that macrocyclization is a clinically validated drug discovery strategy when targeting the kinome.
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