posted on 2016-08-29, 00:00authored byDominic 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.