Consensus Virtual Screening Identified [1,2,4]Triazolo[1,5‐b]isoquinolines As MELK Inhibitor Chemotypes

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.