title: Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies.
abstract: Histone H3-lysine79 (H3K79) methyltransferase DOT1L plays critical roles in normal cell differentiation as well as initiation of acute leukemia. We used structure- and mechanism-based design to discover several potent inhibitors of DOT1L with IC(50) values as low as 38 nM. These inhibitors exhibit only weak or no activities against four other representative histone lysine and arginine methyltransferases, G9a, SUV39H1, PRMT1 and CARM1. The X-ray crystal structure of a DOT1L-inhibitor complex reveals that the N6-methyl group of the inhibitor, located favorably in a predominantly hydrophobic cavity of DOT1L, provides the observed high selectivity. Structural analysis shows that it will disrupt at least one H-bond and/or have steric repulsion for other histone methyltransferases. These compounds represent novel chemical probes for biological function studies of DOT1L in health and disease.
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.forename: Pinhong
authors.initials: P
authors.lastname: Chen
authors.forename: Jiasheng
authors.initials: J
authors.lastname: Diao
authors.forename: Gang
authors.initials: G
authors.lastname: Cheng
authors.forename: Lisheng
authors.initials: L
authors.lastname: Deng
authors.forename: Justin L
authors.initials: JL
authors.lastname: Anglin
authors.forename: B V Venkataram
authors.initials: BV
authors.lastname: Prasad
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
mesh_terms: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D020128:Inhibitory Concentration 50; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure
chemical_list: D004791:Enzyme Inhibitors; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase