title: Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1).
abstract: WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement of the MLL1 gene is associated with onset and progression of acute myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding of small molecule ligands to WDR5 can modulate its interaction with MLL1, suppressing MLL1 methyltransferase activity. Initial structure-activity relationship studies identified N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and selective antagonists of this protein-protein interaction. Guided by crystal structure data and supported by in silico library design, we optimized the scaffold by varying the C-1 benzamide and C-5 substituents. This allowed us to develop the first highly potent (Kdisp < 100 nM) small molecule antagonists of the WDR5-MLL1 interaction and demonstrate that N-(4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide 16d (OICR-9429) is a potent and selective chemical probe suitable to help dissect the biological role of WDR5.
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research , 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Matthäus
authors.initials: M
authors.lastname: Getlik
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Smil
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research , 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Carlos
authors.initials: C
authors.lastname: Zepeda-Velázquez
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Bolshan
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research , 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.|Leslie Dan Faculty of Pharmacy, University of Toronto , 144 College Street, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Gennady
authors.initials: G
authors.lastname: Poda
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Kuznetsova
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research , 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Marcellus
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Senisterra
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Dombrovski
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Taraneh
authors.initials: T
authors.lastname: Hajian
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research , 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Taira
authors.initials: T
authors.lastname: Kiyota
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.|Department of Pharmacology and Toxicology, University of Toronto , Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.|Department of Pharmacology and Toxicology, University of Toronto , Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research , 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.|Department of Pharmacology and Toxicology, University of Toronto , Medical Sciences Building, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Rima
authors.initials: R
authors.lastname: Al-Awar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D004095:Dihydropyridines; D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; C000601920:OICR-9429; D054852:Small Molecule Libraries; C502547:WDR5 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase