title: Synthesis and structure-activity relationship investigation of adenosine-containing inhibitors of histone methyltransferase DOT1L.
abstract: Histone3-lysine79 (H3K79) methyltransferase DOT1L has been found to be a drug target for acute leukemia with MLL (mixed lineage leukemia) gene translocations. A total of 55 adenosine-containing compounds were designed and synthesized, among which several potent DOT1L inhibitors were identified with K(i) values as low as 0.5 nM. These compounds also show high selectivity (>4500-fold) over three other histone methyltransferases. Structure-activity relationships (SAR) of these compounds for their inhibitory activities against DOT1L are discussed. Potent DOT1L inhibitors exhibit selective activity against the proliferation of MLL-translocated leukemia cell lines MV4;11 and THP1 with EC(50) values of 4-11 μM. Isothermal titration calorimetry studies showed that two representative inhibitors bind with a high affinity to the DOT1L:nucleosome complex and only compete with the enzyme cofactor SAM (S-adenosyl-L-methionine) but not the substrate nucleosome.
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Anglin
authors.forename: Lisheng
authors.initials: L
authors.lastname: Deng
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.forename: Guobin
authors.initials: G
authors.lastname: Cai
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Gang
authors.initials: G
authors.lastname: Cheng
authors.forename: Pinhong
authors.initials: P
authors.lastname: Chen
authors.forename: Shuo
authors.initials: S
authors.lastname: Dong
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
mesh_terms: D000241:Adenosine / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D000241:Adenosine