Name
Title | ||
|---|---|---|
Identification of Novel Disruptor of Telomeric Silencing 1-like (DOT1L) Inhibitors through Structure-Based Virtual Screening and Biological Assays. |
Abstract | ||
|---|---|---|
Histone methyltransferases are involved in many important biological processes, and abnormalities in these enzymes are associated with tumorigenesis and progression. Disruptor of telomeric silencing 1-like (DOT1L), a key hub in histone lysine methyltransferases, has been reported to play an important role in the processes of mixed-lineage leukemia (MLL)-rearranged leukemias and validated to be a potential therapeutic target. In this study, we identified, a novel DOT1L inhibitor, DC_L115 (CAS no. 1163729-79-0), by combining structure-based virtual screening with biochemical analyses. This potent inhibitor DC_L115 shows high inhibitory activity toward DOT1L (IC50 = 1.5 mu M). Through a process of surface plasmon resonance-based binding assays, DC_L115 was founded to bind to DOT1L with a binding affinity of 0.6 mu M in vitro. Moreover, this compound selectively inhibits MLL-rearranged cell proliferation with an IC50 value of 37.1 mu M. We further predicted the binding modes of DC_L115 through molecular docking analysis and found that the inhibitor competitively occupies the binding site of S-adenosylmethionine. Overall, this study demonstrates the development of potent DOT1L inhibitors with novel scaffolds. |
Year | DOI | Venue |
|---|---|---|
2016 | 10.1021/acs.jcim.5b00738 | JOURNAL OF CHEMICAL INFORMATION AND MODELING |
Field | DocType | Volume |
DOT1L,Docking (molecular),Gene silencing,Histone,Histone methyltransferase,Ligand (biochemistry),Methyltransferase,Chemistry,Bioinformatics,Virtual screening | Journal | 56 |
Issue | ISSN | Citations |
3 | 1549-9596 | 1 |
PageRank | References | Authors |
0.35 | 1 | 17 |
Name | Order | Citations | PageRank |
|---|---|---|---|
| Shijie Chen | 1 | 1 | 0.35 |
| Linjuan Li | 2 | 1 | 0.35 |
| Yantao Chen | 3 | 1 | 0.35 |
| Junchi Hu | 4 | 1 | 0.35 |
| Jingqiu Liu | 5 | 1 | 0.35 |
| Yu-Chih Liu | 6 | 1 | 0.69 |
| Rongfeng Liu | 7 | 1 | 0.69 |
| Yuanyuan Zhang | 8 | 1 | 0.35 |
| Fanwang Meng | 9 | 1 | 0.35 |
| Kongkai Zhu | 10 | 1 | 1.37 |
| Junyan Lu | 11 | 1 | 0.69 |
| Mingyue Zheng | 12 | 78 | 11.14 |
| Kaixian Chen | 13 | 136 | 12.69 |
| Jin Zhang | 14 | 1 | 0.35 |
| Hualiang Jiang | 15 | 306 | 25.98 |
| Zhiyi Yao | 16 | 1 | 0.35 |
| Cheng Luo | 17 | 29 | 7.86 |