Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Wenyu Yu, Emma J. Chory, Amy K. Wernimont, Wolfram Tempel, Alex Scopton, Alexander Federation, Jason J. Marineau, Jun Qi, Dalia Barsyte-Lovejoy, Joanna Yi, Richard Marcellus, Roxana E. Iacob, John R. Engen, Carly Griffin, Ahmed Aman, Erno Wienholds, Fengling Li, Javier Pineda, Guillermina Estiu, Tatiana Shatseva, Taraneh Hajian, Rima Al-awar, John E. Dick, Masoud Vedadi, Peter J. Brown, Cheryl H. Arrowsmith (), James E. Bradner () and Matthieu Schapira ()
Additional contact information
Wenyu Yu: Structural Genomics Consortium, University of Toronto
Emma J. Chory: Dana-Farber Cancer Institute
Amy K. Wernimont: Structural Genomics Consortium, University of Toronto
Wolfram Tempel: Structural Genomics Consortium, University of Toronto
Alex Scopton: Structural Genomics Consortium, University of Toronto
Alexander Federation: Dana-Farber Cancer Institute
Jason J. Marineau: Dana-Farber Cancer Institute
Jun Qi: Dana-Farber Cancer Institute
Dalia Barsyte-Lovejoy: Structural Genomics Consortium, University of Toronto
Joanna Yi: Dana-Farber Cancer Institute
Richard Marcellus: Medicinal Chemistry Platform, Ontario Institute for Cancer Research
Roxana E. Iacob: Northeastern University
John R. Engen: Northeastern University
Carly Griffin: Medicinal Chemistry Platform, Ontario Institute for Cancer Research
Ahmed Aman: Medicinal Chemistry Platform, Ontario Institute for Cancer Research
Erno Wienholds: Campbell Family Institute, Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, University of Toronto
Fengling Li: Structural Genomics Consortium, University of Toronto
Javier Pineda: Dana-Farber Cancer Institute
Guillermina Estiu: University of Notre Dame
Tatiana Shatseva: Structural Genomics Consortium, University of Toronto
Taraneh Hajian: Structural Genomics Consortium, University of Toronto
Rima Al-awar: Medicinal Chemistry Platform, Ontario Institute for Cancer Research
John E. Dick: Campbell Family Institute, Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, University of Toronto
Masoud Vedadi: Structural Genomics Consortium, University of Toronto
Peter J. Brown: Structural Genomics Consortium, University of Toronto
Cheryl H. Arrowsmith: Structural Genomics Consortium, University of Toronto
James E. Bradner: Dana-Farber Cancer Institute
Matthieu Schapira: Structural Genomics Consortium, University of Toronto

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms2304

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