Identification of 8-Hydroxyquinoline Derivatives Active Against Somatic V658F Mutant JAK1-Dependent Cells

• Published in: Archiv der Pharmazie (Weinheim) 2016-12, Vol.349 (12), p.925-933
• Main Authors: Kiss, Róbert, Bajusz, Dávid, Baskin, Rebekah, Tóth, Katalin, Monostory, Katalin, Sayeski, Peter P., Keserű, György M.
• Format: Article
• Language: English
• Subjects: Animals; Cell Death - drug effects; Cells, Cultured; Docking; JAK1 inhibitor; Janus kinase; Janus Kinase 1 - antagonists & inhibitors; Mice; Molecular Docking Simulation; Mutation; Oxyquinoline - analogs & derivatives; Oxyquinoline - chemical synthesis; Oxyquinoline - pharmacology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Rats; Structure-Activity Relationship; V658F/JAK1 cells; Virtual screening
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201600246

Janus kinases (JAKs) and their gain‐of‐function mutants have been implicated in a range of oncological, inflammatory, and autoimmune conditions, which has sparked great research interest in the discovery and development of small‐molecule JAK inhibitors. Two molecules are currently marketed as JAK inhibitors, but due to the displayed side effects (owing to their suboptimal selectivities among the various JAK subtypes) new JAK inhibitors are still sought after. We present the results of an extensive virtual screening campaign based on a multi‐step screening protocol involving ligand docking. The screening yielded five new, experimentally validated inhibitors of JAK1 with 8‐hydroxyquinoline as a novel hinge‐binding scaffold. The compounds did not only display favorable potencies in a JAK1V658F‐driven cell‐based assay but were also shown to be non‐cytotoxic on rat liver cells. An extensive virtual screening campaign was carried out, resulting in multiple novel JAK1 inhibitors with the 8‐hydroxyquinoline scaffold as the hinge‐binding motif. The compounds have been shown to inhibit JAK1V658F‐driven cell growth and to be non‐cytotoxic to rat liver cells. Hence, they represent valuable starting points for JAK1V658F‐involving disease conditions, including acute lymphoblastic leukemia.