Journal Article

Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Estiu, Guillermina, Marineau, Jason J., Barsyte-Lovejoy, Dalia, Vedadi, Masoud, Yi, Joanna, Wienholds, Erno, Engen, John R., Scopton, Alex, Tempel, Wolfram, Iacob, Roxana E., Aman, Ahmed, Marcellus, Richard, Dick, John E., Bradner, James E., Al-awar, Rima, Li, Fengling, Shatseva, Tatiana, Federation, Alexander, Griffin, Carly, Pineda, Javier, Wernimont, Amy K., Yu, Wenyu, Qi, Jun, Brown, Peter J., Arrowsmith, Cheryl H., Chory, Emma J., Hajian, Taraneh, Schapira, Matthieu

2012

Overview

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. Selective inhibitors of protein methyltransferases are anticancer drug candidates. Yu et al . report the structural changes that occur when selective inhibitors bind to the protein methyltransferase DOT1L.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/436/1729 / 631/45/535 / Adenosine - analogs & derivatives / Adenosine - pharmacology / Adenosylmethionine / Binding, Competitive - drug effects / biological sciences / Blotting, Western / Bromination / Catalysis / Catalytic Domain - drug effects / chemical biology / Fusion protein / Humanities and Social Sciences / Humans / Inhibitors / Kinases / Kinetics / Leukemia / Methyltransferase / Methyltransferases - antagonists & inhibitors / Methyltransferases - metabolism / multidisciplinary / Phenylurea Compounds - pharmacology / Protein structure / Proteins / S-Adenosylmethionine / Science / Structure-Activity Relationship / Substrate Specificity / Surface Plasmon Resonance