Hit-to-lead studies on benzimidazole inhibitors of ITK: Discovery of a novel class of kinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2007-07, Vol.17 (13), p.3660-3665
• Main Authors: Snow, Roger J., Abeywardane, Asitha, Campbell, Scot, Lord, John, Kashem, Mohammed A., Khine, Hnin Hnin, King, Josephine, Kowalski, Jennifer A., Pullen, Steven S., Roma, Teresa, Roth, Gregory P., Sarko, Christopher R., Wilson, Noel S., Winters, Michael P., Wolak, John P., Cywin, Charles L.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - chemistry; Benzimidazole; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Binding Sites; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Chemistry, Pharmaceutical - methods; Drug Evaluation, Preclinical - methods; Enzyme Inhibitors - pharmacology; Humans; Hydrogen Bonding; Immunomodulators; Inducible T cell kinase; Inhibitory Concentration 50; ITK; Kinase; Kinase inhibitor; Medical sciences; Models, Chemical; Pharmacology. Drug treatments; Protein Binding; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein-Tyrosine Kinases - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.04.045

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.