2. Academic Validation
  3. Identification and Validation of 3-Cyano-Quinoline Ligands Targeting Integrin-Linked Kinase (ILK)

Identification and Validation of 3-Cyano-Quinoline Ligands Targeting Integrin-Linked Kinase (ILK)

  • J Med Chem. 2026 Jun 11;69(11):12982-13001. doi: 10.1021/acs.jmedchem.5c03773.
Francesco Aleksy Greco 1 2 3,  Kamal Rayees Abdul Azeez 1 2,  Marko Mitrović 1 2,  Saran Aswathaman Sivashanmugam 1 2,  Martin Peter Schwalm 1 2 3,  Franziska Preuss 1 2,  Deep Chatterjee 1 2,  Viktoria Morasch 1 2,  Sebastian Mathea 1 2,  Thomas Hanke 1 2,  Susanne Müller 1 2,  Stefan Knapp 1 2 3
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.
  • 2 Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences (BMLS), Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany.
  • 3 German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
PMID: 42185966 DOI: 10.1021/acs.jmedchem.5c03773
Abstract

Integrin-linked kinase (ILK) is a pseudokinase that directly interacts with β-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 (KD = ∼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.

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