American Chemical Society
Browse

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

Download (1.19 MB)
journal contribution
posted on 2016-08-29, 00:00 authored by Dominic Tisi, Elisabetta Chiarparin, Emiliano Tamanini, Puja Pathuri, Joseph E. Coyle, Adam Hold, Finn P. Holding, Nader Amin, Agnes C. L. Martin, Sharna J. Rich, Valerio Berdini, Jeff Yon, Paul Acklam, Rosemary Burke, Ludovic Drouin, Jenny E. Harmer, Fiona Jeganathan, Rob L. M. van Montfort, Yvette Newbatt, Marcello Tortorici, Maura Westlake, Amy Wood, Swen Hoelder, Tom D. Heightman
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.

History