title: Small-molecule inhibition of MLL activity by disruption of its interaction with WDR5.
abstract: WDR5 (WD40 repeat protein 5) is an essential component of the human trithorax-like family of SET1 [Su(var)3-9 enhancer-of-zeste trithorax 1] methyltransferase complexes that carry out trimethylation of histone 3 Lys4 (H3K4me3), play key roles in development and are abnormally expressed in many cancers. In the present study, we show that the interaction between WDR5 and peptides from the catalytic domain of MLL (mixed-lineage leukaemia protein) (KMT2) can be antagonized with a small molecule. Structural and biophysical analysis show that this antagonist binds in the WDR5 peptide-binding pocket with a Kd of 450 nM and inhibits the catalytic activity of the MLL core complex in vitro. The degree of inhibition was enhanced at lower protein concentrations consistent with a role for WDR5 in directly stabilizing the MLL multiprotein complex. Our data demonstrate inhibition of an important protein-protein interaction and form the basis for further development of inhibitors of WDR5-dependent enzymes implicated in MLL-rearranged leukaemias or other cancers.
authors.affiliation: Structural Genomics Consortium, 101 College Street, Toronto, Ontario, Canada.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Senisterra
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Abdellah
authors.initials: A
authors.lastname: Allali-Hassani
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Wasney
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte-Lovejoy
authors.forename: Ludmila
authors.initials: L
authors.lastname: Dombrovski
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
authors.forename: Kong T
authors.initials: KT
authors.lastname: Nguyen
authors.forename: David
authors.initials: D
authors.lastname: Smil
authors.forename: Yuri
authors.initials: Y
authors.lastname: Bolshan
authors.forename: Taraneh
authors.initials: T
authors.lastname: Hajian
authors.forename: Hao
authors.initials: H
authors.lastname: He
authors.forename: Alma
authors.initials: A
authors.lastname: Seitova
authors.forename: Irene
authors.initials: I
authors.lastname: Chau
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Poda
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Couture
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.forename: Rima
authors.initials: R
authors.lastname: Al-Awar
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
mesh_terms: D020134:Catalytic Domain / Q000502:physiology; D018360:Crystallography, X-Ray; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; C502547:WDR5 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase