title: Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction.
abstract: The WD40-repeat protein WDR5 plays a critical role in maintaining the integrity of MLL complexes and fully activating their methyltransferase function. MLL complexes, the trithorax-like family of SET1 methyltransferases, catalyze trimethylation of lysine 4 on histone 3, and they have been widely implicated in various cancers. Antagonism of WDR5 and MLL subunit interaction by small molecules has recently been presented as a practical way to inhibit activity of the MLL1 complex, and N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides were reported as potent and selective antagonists of such an interaction. Here, we describe the protein crystal structure guided optimization of prototypic compound 2 (K dis = 7 μM), leading to identification of more potent antagonist 47 (K dis = 0.3 μM).
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: Medicinal Chemistry Platform, Ontario Institute for Cancer Research , 101 College Street, MaRS Centre, South 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: Ekaterina
authors.initials: E
authors.lastname: Kuznetsova
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wasney
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: Medicinal Chemistry Platform, Ontario Institute for Cancer Research , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Gennadiy
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: Kong T
authors.initials: KT
authors.lastname: Nguyen
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: 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: 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: 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: 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: Medicinal Chemistry Platform, Ontario Institute for Cancer Research , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Rima
authors.initials: R
authors.lastname: Al-Awar
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, MaRS Centre, South Tower, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
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
keywords: MLL; SET1 methyltransferase complex; WDR5; peptide binding site; small molecule antagonists