1. Hit-to-lead studies on benzimidazole inhibitors of ITK: discovery of a novel class of kinase inhibitors.
- Author
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Snow RJ, Abeywardane A, Campbell S, Lord J, Kashem MA, Khine HH, King J, Kowalski JA, Pullen SS, Roma T, Roth GP, Sarko CR, Wilson NS, Winters MP, Wolak JP, and Cywin CL
- Subjects
- Adenosine Triphosphate chemistry, Benzimidazoles chemical synthesis, Binding Sites, Drug Evaluation, Preclinical methods, Enzyme Inhibitors pharmacology, Humans, Hydrogen Bonding, Inhibitory Concentration 50, Models, Chemical, Protein Binding, Protein Kinase Inhibitors chemistry, Structure-Activity Relationship, Benzimidazoles chemistry, Chemistry, Pharmaceutical methods, Protein Kinase Inhibitors chemical synthesis, Protein-Tyrosine Kinases antagonists & inhibitors
- Abstract
Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.
- Published
- 2007
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