Discovery of Novel Disruptor of Silencing Telomeric 1-Like (DOTI L) Inhibitors using a Target-Specific Scoring Function for the (S)-Adenosyl-L-methionine (SAM)-Dependent Methyltransferase Family

The disruptor of telomeric silencing 1-like (DOT1L) protein is a histone H3K79 methyltransferase that plays a key role in transcriptional elongation and cell cycle regulation and is required for the development and maintenance of MLL-rearranged mixed lineage leukemia. Much effort has been dedicated toward discovering novel scaffold DOT1L inhibitors using different strategies. Here, we report the development and application of a target-specific scoring function, the SAM score, for (S)-adenosyl-Lmethionine (SAM)-dependent methyltransferases, for the discovery of novel DOT1L inhibitors. On the basis of the SAM score, we successfully identified a novel class of DOTIL inhibitors with a scaffold of [1,2,4]-triazolo-[3,4-b] [1,3,4]-thiadiazole, in which compound 6 exhibits an IC50 value of 8.3 mu M with selectivity versus other tested SAM -dependent methyltransferases. In cellular studies, 6 selectively targets DOT1L, blocks the proliferation of mixed lineage leukemia cell lines, and causes cell cycle arrest and apoptosis. Moreover, we analyzed the putative binding modes of 6 and its analogues obtained by molecular docking, which may assist with the future development of DOT1L inhibitors with improved potency and selectivity profiles.Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12050201]; National Basic Research Program [2015CB910304]; National Natural Science Foundation of China [21210003, 81230076, 81430084]; National Key Research & Development Plan [2016YF1201003]; Fund of State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science [TMC201505]; State Key Laboratory of Natural and Biomimetic DrugsSCI(E)ARTICLE52026-20366