Abstact

Integrin-linked kinase (ILK) is a pseudokinase that directly interacts with beta-integrins and plays a pivotal role in regulating focal adhesion function. ILK has been implicated in the development of various diseases, particularly cancer. However, currently, no validated ligands for ILK have been reported. Here, we describe the identification of 3-cyano-quinolines that potently bind to ILK (K(D) = approximately 250 nM), and crystallographic studies revealed a type I binding mode. A medicinal chemistry campaign exploring structure-activity relationships (SAR) using a robust parallel synthesis approach provided comprehensive SAR and identified regions amenable to modification. In addition, we demonstrated that the optimized 3-cyano-quinoline 1 (DHP) modulates actin cytoskeletal dynamics. This work highlights the first validated ILK ligands and establishes a foundation for future translational efforts, such as the development of selective PROTACs targeting ILK for degradation by the ubiquitin system.