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Title: Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors

Journal Article · · Nature Communications
DOI:https://doi.org/10.1038/ncomms2304· OSTI ID:1062437
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  1. Univ. of Toronto, ON (Canada)
  2. Dana-Farber Cancer Inst., Boston, MA (United States); Northeastern Univ., Boston, MA (United States)
  3. Dana-Farber Cancer Inst., Boston, MA (United States)
  4. Ontario Inst. for Cancer Research, Toronto, ON (Canada)
  5. Northeastern Univ., Boston, MA (United States)
  6. Dana-Farber Cancer Inst., Boston, MA (United States); Univ. of Notre Dame, IN (United States)
  7. Univ. of Notre Dame, IN (United States)
  8. Dana-Farber Cancer Inst., Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
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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 toEPZ004777, 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.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI ID:
1062437
Journal Information:
Nature Communications, Vol. 3, Issue 2012; ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH

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Related Subjects

biological sciences
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