Energetic dissection of Gleevec's selectivity toward human tyrosine kinases

• Published in: Nature structural & molecular biology Vol. 21; no. 10; pp. 848 - 853
• Main Authors: Agafonov, Roman V, Wilson, Christopher, Otten, Renee, Buosi, Vanessa, Kern, Dorothee
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2014; Nature Publishing Group
• Subjects: 631/45/173; 631/45/275; 631/57/2272/1590; 692/699; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzamides - chemistry; Benzamides - pharmacology; Biochemistry; Biological Microscopy; Cell Line; Cellular control mechanisms; Chemotherapy; Enzymes; Genetic aspects; Humans; Imatinib Mesylate; Kinases; Kinetics; Life Sciences; Membrane Biology; Neoplasms - enzymology; Pharmacology; Phosphotransferases; Piperazines - chemistry; Piperazines - pharmacology; Plasticity; Properties; Protein Binding; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein research; Protein Structure; Protein Structure, Tertiary; Proteins; Proto-Oncogene Proteins c-abl - antagonists & inhibitors; Proto-Oncogene Proteins c-abl - chemistry; Pyrimidines - chemistry; Pyrimidines - pharmacology; Regulation; src-Family Kinases - ultrastructure; Thermodynamics
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.2891

Chemotherapeutic drug Gleevec (imatinib) is a potent and specific inhibitor of Abl kinase. NMR and fast kinetic analyses now reveal that Abl undergoes an induced-fit conformational change upon Gleevec binding. Protein kinases are obvious drug targets against cancer, owing to their central role in cellular regulation. Since the discovery of Gleevec, a potent and specific inhibitor of Abl kinase, as a highly successful cancer therapeutic, the ability of this drug to distinguish between Abl and other tyrosine kinases such as Src has been intensely investigated but without much success. Using NMR and fast kinetics, we establish a new model that solves this longstanding question of how the two tyrosine kinases adopt almost identical structures when bound to Gleevec but have vastly different affinities. We show that, in contrast to all other proposed models, the origin of Abl's high affinity lies predominantly in a conformational change after binding. An energy landscape providing tight affinity via an induced fit and binding plasticity via a conformational-selection mechanism is likely to be general for many inhibitors.