Journal
NATURE COMMUNICATIONS
Volume 3, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms2304
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Funding
- National Science Foundation [OCI-1053575]
- National Cancer Institute [Y1-CO-1020]
- National Institute of General Medical Sciences [Y1-GM-1104]
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- Leukaemia and Lymphoma Society (SCOR)
- National Institutes of Health [R01 CA152314, K08CA128972]
- American Society of Hematology
- William Lawrence and Blanche Hughes Foundation
- Steamboat Foundation Award
- Northeastern University
- Barnett Institute of Chemical and Biological Analysis
- NIH [R01-GM086507]
- Canadian Institutes of Health Research, Eli Lilly Canada
- Genome Canada
- GlaxoSmithKline
- Ontario Ministry of Economic Development and Innovation
- Novartis Research Foundation
- Pfizer
- AbbVie
- Takeda
- Wellcome Trust
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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.
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