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Structure of the Epigenetic Oncogene MMSET and Inhibition by N -Alkyl Sinefungin Derivatives

DOI: 10.1021/acschembio.6b00308 DOI Help

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.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: ESRF