2. Academic Validation
  3. Kinase inhibitor macrocycles: a perspective on limiting conformational flexibility when targeting the kinome with small molecules

Kinase inhibitor macrocycles: a perspective on limiting conformational flexibility when targeting the kinome with small molecules

  • RSC Med Chem. 2023 Dec 12;15(2):399-415. doi: 10.1039/d3md00457k.
Baku Acharya 1,  Debasmita Saha 1 2,  Daniel Armstrong 1,  Baha'a Jabali 1,  Maha Hanafi 1 3,  Alan Herrera-Rueda 1,  Naga Rajiv Lakkaniga 4,  Brendan Frett 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences Little Rock AR USA [email protected].
  • 2 Conrad Prebys Centre for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute San Diego CA USA.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University Cairo 11526 Egypt.
  • 4 Department of Chemistry and Chemical Biology, Indian Institute of Technology (Indian School of Mines) Dhanbad India.
PMID: 38389874 DOI: 10.1039/d3md00457k
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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