Synthesis and Structure鈥揂ctivity Relationship Investigation of Adenosine-Containing Inhibitors of Histone Methyltransferase DOT1L
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- 作者：Justin L. Anglin ; Lisheng Deng ; Yuan Yao ; Guobin Cai ; Zhen Liu ; Hong Jiang ; Gang Cheng ; Pinhong Chen ; Shuo Dong ; Yongcheng Song
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：September 27, 2012
- 年：2012
- 卷：55
- 期：18
- 页码：8066-8074
- 全文大小：425K
- 年卷期：v.55,no.18(September 27, 2012)
- ISSN：1520-4804
文摘
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 Ki values as low as 0.5 nM. These compounds also show high selectivity (>4500-fold) over three other histone methyltransferases. Structure鈥揳ctivity 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 EC50 values of 4鈥?1 渭M. 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.