title: Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors.
abstract: Selective inhibition of protein methyltransferases is a promising new approach to drug discovery. An attractive strategy towards this goal is the development of compounds that selectively inhibit binding of the cofactor, S-adenosylmethionine, within specific protein methyltransferases. Here we report the three-dimensional structure of the protein methyltransferase DOT1L bound to EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy. This structure and those of four new analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage leukaemia cells, in which DOT1L is aberrantly localized via interaction with an oncogenic MLL fusion protein. These data provide important new insight into mechanisms of cell-active S-adenosylmethionine-competitive protein methyltransferase inhibitors, and establish a foundation for the further development of drug-like inhibitors of DOT1L for cancer therapy.
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Yu
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Chory
authors.forename: Amy K
authors.initials: AK
authors.lastname: Wernimont
authors.forename: Wolfram
authors.initials: W
authors.lastname: Tempel
authors.forename: Alex
authors.initials: A
authors.lastname: Scopton
authors.forename: Alexander
authors.initials: A
authors.lastname: Federation
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Marineau
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte-Lovejoy
authors.forename: Joanna
authors.initials: J
authors.lastname: Yi
authors.forename: Richard
authors.initials: R
authors.lastname: Marcellus
authors.forename: Roxana E
authors.initials: RE
authors.lastname: Iacob
authors.forename: John R
authors.initials: JR
authors.lastname: Engen
authors.forename: Carly
authors.initials: C
authors.lastname: Griffin
authors.forename: Ahmed
authors.initials: A
authors.lastname: Aman
authors.forename: Erno
authors.initials: E
authors.lastname: Wienholds
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.forename: Javier
authors.initials: J
authors.lastname: Pineda
authors.forename: Guillermina
authors.initials: G
authors.lastname: Estiu
authors.forename: Tatiana
authors.initials: T
authors.lastname: Shatseva
authors.forename: Taraneh
authors.initials: T
authors.lastname: Hajian
authors.forename: Rima
authors.initials: R
authors.lastname: Al-Awar
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D015153:Blotting, Western; D002384:Catalysis; D020134:Catalytic Domain / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007700:Kinetics; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance
chemical_list: C581325:EPZ004777; D010671:Phenylurea Compounds; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D000241:Adenosine