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 ShatsevaTaraneh Hajian, Rima Al-Awar, John E. Dick, Masoud Vedadi, Peter J. Brown, Cheryl H. Arrowsmith, James E. Bradner, Matthieu Schapira

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236 Scopus citations


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.

Original languageEnglish
Article number1288
JournalNature Communications
StatePublished - 2012
Externally publishedYes


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