Consensus Virtual Screening Identified [1, 2, 4]Triazolo[1, 5‐b]isoquinolines As MELK Inhibitor Chemotypes. (19th October 2021)

• Record Type: Journal Article
• Authors: Rácz, Anita; Palkó, Roberta; Csányi, Dorottya; Riedl, Zsuzsanna; Bajusz, Dávid; Keserű, György M.
• Is Part Of: ChemMedChem. Volume 17:Number 2(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-10-19
• Subjects: MELK inhibitor -- virtual screening -- kinase -- docking -- isoquinoline; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100569
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Maternal Embryonic Leucine‐zipper Kinase (MELK) is a current oncotarget involved in a diverse range of human cancers, with the usage of MELK inhibitors being explored clinically. Here, we aimed to discover new MELK inhibitor chemotypes from our in‐house compound library with a consensus‐based virtual screening workflow, employing three screening concepts. After careful retrospective validation, prospective screening and in vitro enzyme inhibition testing revealed a series of [1, 2, 4]triazolo[1, 5‐ b ]isoquinolines as a new structural class of MELK inhibitors, with the lead compound of the series exhibiting a sub‐micromolar inhibitory activity. The structure‐activity relationship of the series was explored by testing further analogs based on a structure‐guided selection process. Importantly, the present work marks the first disclosure of the synthesis and bioactivity of this class of compounds. Abstract : New MELK inhibitor chemotype : This study documents the first medicinal chemical usage of the [1, 2, 4]triazolo[1, 5‐ b ]isoquinoline scaffold, resulting from a virtual screening campaign to identify new inhibitors of the MELK kinase. Structure−activity relationships are observed and syntheses for 19 analogues are reported.