title: Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives.
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.
authors: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, United Kingdom CB4 0QA.
authors: Dominic
authors: D
authors: Tisi
authors: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, United Kingdom CB4 0QA.
authors: Elisabetta
authors: E
authors: Chiarparin
authors: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, United Kingdom CB4 0QA.
authors: Emiliano
authors: E
authors: Tamanini
authors: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, United Kingdom CB4 0QA.
authors: Puja
authors: P
authors: Pathuri
authors: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, United Kingdom CB4 0QA.
authors: Joseph E
authors: JE
authors: Coyle
authors: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, United Kingdom CB4 0QA.
authors: Adam
authors: A
authors: Hold
authors: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, United Kingdom CB4 0QA.
authors: Finn P
authors: FP
authors: Holding
authors: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, United Kingdom CB4 0QA.
authors: Nader
authors: N
authors: Amin
authors: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, United Kingdom CB4 0QA.
authors: Agnes C L
authors: AC
authors: Martin
authors: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, United Kingdom CB4 0QA.
authors: Sharna J
authors: SJ
authors: Rich
authors: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, United Kingdom CB4 0QA.
authors: Valerio
authors: V
authors: Berdini
authors: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, United Kingdom CB4 0QA.
authors: Jeff
authors: J
authors: Yon
authors: CRUK Cancer Therapeutics Unit, Institute of Cancer Research , 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG.
authors: Paul
authors: P
authors: Acklam
authors: CRUK Cancer Therapeutics Unit, Institute of Cancer Research , 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG.
authors: Rosemary
authors: R
authors: Burke
authors: CRUK Cancer Therapeutics Unit, Institute of Cancer Research , 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG.
authors: Ludovic
authors: L
authors: Drouin
authors: CRUK Cancer Therapeutics Unit, Institute of Cancer Research , 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG.
authors: Jenny E
authors: JE
authors: Harmer
authors: CRUK Cancer Therapeutics Unit, Institute of Cancer Research , 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG.
authors: Fiona
authors: F
authors: Jeganathan
authors: CRUK Cancer Therapeutics Unit, Institute of Cancer Research , 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG.
authors: Rob L M
authors: RL
authors: van Montfort
authors: CRUK Cancer Therapeutics Unit, Institute of Cancer Research , 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG.
authors: Yvette
authors: Y
authors: Newbatt
authors: CRUK Cancer Therapeutics Unit, Institute of Cancer Research , 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG.
authors: Marcello
authors: M
authors: Tortorici
authors: CRUK Cancer Therapeutics Unit, Institute of Cancer Research , 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG.
authors: Maura
authors: M
authors: Westlake
authors: CRUK Cancer Therapeutics Unit, Institute of Cancer Research , 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG.
authors: Amy
authors: A
authors: Wood
authors: CRUK Cancer Therapeutics Unit, Institute of Cancer Research , 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG.
authors: Swen
authors: S
authors: Hoelder
authors: Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, United Kingdom CB4 0QA.
authors: Tom D
authors: TD
authors: Heightman
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002151:Calorimetry; D002853:Chromatography, Liquid; D018360:Crystallography, X-Ray; D015195:Drug Design; D044127:Epigenesis, Genetic; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009857:Oncogenes; D011487:Protein Conformation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D012097:Repressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; D000241:Adenosine; C006235:sinefungin