biostudies-literatureUnknown6(1)Johnson CNA novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper kinase (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by protein-ligand X-ray crystallography and incorporation of a slender linkage capable of bypassing a large gate-keeper residue, thus enabling design of molecules accessing both hinge and induced pocket regions. Optimization of an initial hit led to the identification of a low-nanomolar, cell-penetrant Type II inhibitor suitable for use as a chemical probe for MELK.ACS medicinal chemistry letters31-6https://www.ebi.ac.uk/biostudies/studies/S-EPMC4291807biostudies-literatureStructure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase.PMC4291807Adelinet CMcMenamin RRees DCBerdini VFrederickson MFreyne EJBeke LCoyle JEDay PJMeerpoel LBrehmer DMevellec LHoward SPasquier ELinders JTGilissen RAPatel SBonnet PCalo FHamlett CCJohnson CNfalseStructure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase.A novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper kinase (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by protein-ligand X-ray crystallography and incorporation of a slender linkage capable of bypassing a large gate-keeper residue, thus enabling design of molecules accessing both hinge and induced pocket regions. Optimization of an initial hit led to the identification of a low-nanomolar, cell-penetrant Type II inhibitor suitable for use as a chemical probe for MELK.2015-01-01T00:00:00Z2015 Jan2026-05-03T06:52:22.712Z2019-03-27T01:43:19ZS-EPMC42918072558992610.1021/ml5001273