title: Identification and Structure-Activity Relationship Studies of Small-Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1.
abstract: The methyllysine reader protein Spindlin1 has been implicated in the tumorigenesis of several types of cancer and may be an attractive novel therapeutic target. Small-molecule inhibitors of Spindlin1 should be valuable as chemical probes as well as potential new therapeutics. We applied an iterative virtual screening campaign, encompassing structure- and ligand-based approaches, to identify potential Spindlin1 inhibitors from databases of commercially available compounds. Our in silico studies coupled with in vitro testing were successful in identifying novel Spindlin1 inhibitors. Several 4-aminoquinazoline and quinazolinethione derivatives were among the active hit compounds, which indicated that these scaffolds represent promising lead structures for the development of Spindlin1 inhibitors. Subsequent lead optimization studies were hence carried out, and numerous derivatives of both lead scaffolds were synthesized. This resulted in the discovery of novel inhibitors of Spindlin1 and helped explore the structure-activity relationships of these inhibitor series.
authors.affiliation: Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120, Halle/Saale, Germany.
authors.forename: Dina
authors.initials: D
authors.lastname: Robaa
authors.affiliation: Institute of Pharmaceutical Sciences, University of Freiburg, 79104, Freiburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Wagner
authors.affiliation: Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120, Halle/Saale, Germany.
authors.forename: Chiara
authors.initials: C
authors.lastname: Luise
authors.affiliation: Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120, Halle/Saale, Germany.
authors.forename: Luca
authors.initials: L
authors.lastname: Carlino
authors.affiliation: Department of Urology and Center for Clinical Research, University of Freiburg Medical Center, 79106, Freiburg, Germany.|Diamond Light Source Ltd., Harwell Science & Innovation Campus, Didcot, Oxfordshire, OX11 0DE, UK.
authors.forename: Joel
authors.initials: J
authors.lastname: McMillan
authors.affiliation: Diamond Light Source Ltd., Harwell Science & Innovation Campus, Didcot, Oxfordshire, OX11 0DE, UK.
authors.forename: Ralf
authors.initials: R
authors.lastname: Flaig
authors.affiliation: Department of Urology and Center for Clinical Research, University of Freiburg Medical Center, 79106, Freiburg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Freiburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.affiliation: Institute of Pharmaceutical Sciences, University of Freiburg, 79104, Freiburg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Freiburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.affiliation: Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120, Halle/Saale, Germany. wolfgang.sippl@pharmazie.uni-halle.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D054852:Small Molecule Libraries; C104434:spindlin
keywords: AlphaLISA assay; Spindlin1; lead optimization; methyllysine readers; virtual screening