A general strategy for creating "inactive-conformation" abl inhibitors.

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Pharmacology

Background:

• Kinase inhibitors are crucial therapeutics, classified as type I or type II based on their binding to the ATP site.
• Type II inhibitors, which bind adjacent to the ATP pocket, have historically relied on structure-activity relationship-guided discovery.
• A general pharmacophore model for type II inhibition was lacking, hindering rational design strategies.

Purpose of the Study:

• To develop a general pharmacophore model for type II kinase inhibition.
• To enable a rational hybrid-design approach for converting type I inhibitors into type II inhibitors.
• To validate the designed type II inhibitors using biochemical, cellular, and structural methods.

Main Methods:

• Development of a general pharmacophore model for type II kinase inhibitors.
• Hybrid-design strategy involving appending a 3-trifluoromethylbenzamide moiety to type I scaffolds.
• Biochemical and cellular kinase assays to assess inhibitory activity.
• X-ray cocrystallography to determine the binding mode of designed inhibitors with Abl kinase.

Main Results:

• A general pharmacophore model for type II inhibition was successfully established.
• Four distinct type I scaffolds were converted into type II inhibitors using the hybrid-design approach.
• The designed compounds demonstrated type II inhibition profiles in biochemical and cellular assays.
• Cocrystallography confirmed the type II binding mode of the designed inhibitors with Abl kinase.

Conclusions:

• The developed pharmacophore model and hybrid-design strategy provide a rational approach for discovering type II kinase inhibitors.
• This method facilitates the conversion of existing type I inhibitors into potent type II counterparts.
• The findings offer new avenues for developing targeted kinase inhibitor therapies.