title: New small molecule inhibitors of histone methyl transferase DOT1L with a nitrile as a non-traditional replacement for heavy halogen atoms.
abstract: A number of new nucleoside derivatives are disclosed as inhibitors of DOT1L activity. SARs established that DOT1L inhibition could be achieved through incorporation of polar groups and small heterocycles at the 5-position (5, 6, 12) or by the application of alternative nitrogenous bases (18). Based on these results, CN-SAH (19) was identified as a potent and selective inhibitor of DOT1L activity where the polar 5-nitrile group was shown by crystallography to bind in the hydrophobic pocket of DOT1L. In addition, we show that a polar nitrile group can be used as a non-traditional replacement for heavy halogen atoms.
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Sophie S
authors.initials: SS
authors.lastname: Spurr
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Elliott D
authors.initials: ED
authors.lastname: Bayle
authors.affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto MG5 1L7, Canada.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Yu
authors.affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto MG5 1L7, Canada.
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto MG5 1L7, Canada.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Tempel
authors.affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto MG5 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto MG5 1A8, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto MG5 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto MG5 1A8, Canada.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK. Electronic address: p.fish@ucl.ac.uk.
authors.forename: Paul V
authors.initials: PV
authors.lastname: Fish
mesh_terms: D003461:Crystallography; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006219:Halogens / Q000737:chemistry*; D011495:Histone-Lysine N-Methyltransferase; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D006219:Halogens; D009570:Nitriles; D054852:Small Molecule Libraries; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
keywords: Bioisostere; Cyano-deaza-SAH; DOT1L inhibitors; Protein methyltransferase; Toyocamycin