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Structure of the epigenetic oncogene MMSET and inhibition by N-alkyl sinefungin derivatives
DOI:
10.1021/acschembio.6b00308
Authors:
Dominic
Tisi
(Astex Pharmaceuticals)
,
Elisabetta
Chiarparin
(Astex Pharmaceuticals)
,
Emiliano
Tamanini
(Astex Pharmaceuticals)
,
Puja
Pathuri
(Astex Pharmaceuticals)
,
Joseph E.
Coyle
(Astex Pharmaceuticals)
,
Adam
Hold
(Astex Pharmaceuticals)
,
Finn P.
Holding
(Astex Pharmaceuticals)
,
Nader
Amin
(Astex Pharmaceuticals)
,
Agnes C. L.
Martin
(Astex Pharmaceuticals)
,
Sharna J.
Rich
(Astex Pharmaceuticals)
,
Valerio
Berdini
(Astex Pharmaceuticals)
,
Jeff
Yon
(Astex Pharmaceuticals)
,
Paul
Acklam
(Institute of Cancer Research)
,
Rosemary
Burke
(Institute of Cancer Research)
,
Ludovic
Drouin
(Institute of Cancer Research)
,
Jenny E.
Harmer
(Institute of Cancer Research)
,
Fiona
Jeganathan
(Institute of Cancer Research)
,
Rob
Van Montfort
(Institute of Cancer Research)
,
Yvette
Newbatt
(Institute of Cancer Research)
,
Marcello
Tortorici
(Institute of Cancer Research)
,
Maura
Westlake
(Institute of Cancer Research)
,
Amy
Wood
(Institute of Cancer Research)
,
Swen
Hoelder
(Institute of Cancer Research)
,
Tom D.
Heightman
(Astex Pharmaceuticals)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Acs Chemical Biology
, VOL 11
, PAGES 3093 - 3105
State:
Published (Approved)
Published:
November 2016
Abstract: The members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using solution phase and crystal structural methods. On the basis of 2D NMR experiments comparing NSD1 and MMSET structural mobility, we designed an MMSET construct with five point mutations in the N-terminal helix of its SET domain for crystallization experiments and elucidated the structure of the mutant MMSET SET domain at 2.1 Å resolution. Both NSD1 and MMSET crystal systems proved resistant to soaking or cocrystallography with inhibitors. However, use of the close homologue SETD2 as a structural surrogate supported the design and characterization of N-alkyl sinefungin derivatives, which showed low micromolar inhibition against both SETD2 and MMSET.
Journal Keywords: Peptides and proteins; Reaction products; Monomers; Crystal structure; Inhibitors
Diamond Keywords: Enzymes; Epigenetics
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Instruments:
I03-Macromolecular Crystallography
,
I04-Macromolecular Crystallography
Other Facilities: ESRF
Added On:
21/04/2017 11:29
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Cancer
Biochemistry
Genetics
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)