Discovery of Novel Disruptor of Silencing Telomeric 1-Like (DOT1L) 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-l-methionine (SAM)-dependent methyltransferases, for the discovery of novel DOT1L inhibitors. On the basis of the SAM score, we successfully identified a novel class of DOT1L inhibitors with a scaffold of [1,2,4]-triazolo-[3,4-b][1,3,4]-thiadiazole, in which compound 6 exhibits an IC50value of 8.3 μM 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.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|State Key Laboratory of Natural and Biomimetic Drugs, Peking University , Beijing 100191, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
Yulan
Y
Wang
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|School of Life Science and Technology, Shanghai Tech University , Shanghai 200031, China.
Linjuan
L
Li
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
Bidong
B
Zhang
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
Jing
J
Xing
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
Shijie
S
Chen
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
Wei
W
Wan
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|Nano Science and Technology Institute, University of Science and Technology of China , Suzhou 215123, China.
Yakai
Y
Song
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
Hao
H
Jiang
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.|School of Life Science and Technology, Shanghai Tech University , Shanghai 200031, China.
Hualiang
H
Jiang
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
Cheng
C
Luo
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
Mingyue
0000-0002-3323-3092
M
Zheng
D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016615:Telomere
D004791:Enzyme Inhibitors; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase