Selective Inhibitors of Histone Methyltransferase DOT1L: Design, Synthesis, and Crystallographic Studies

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• 作者：Yuan Yao ; Pinhong Chen ; Jiasheng Diao ; Gang Cheng ; Lisheng Deng ; Justin L. Anglin ; B. V. Venkataram Prasad ; Yongcheng Song
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：October 26, 2011
• 年：2011
• 卷：133
• 期：42
• 页码：16746-16749
• 全文大小：757K
• 年卷期：v.133,no.42(October 26, 2011)
• ISSN：1520-5126

文摘

Histone H3-lysine79 (H3K79) methyltransferase DOT1L plays critical roles in normal cell differentiation as well as initiation of acute leukemia. We used structure- and mechanism-based design to discover several potent inhibitors of DOT1L with IC₅₀ values as low as 38 nM. These inhibitors exhibit only weak or no activities against four other representative histone lysine and arginine methyltransferases, G9a, SUV39H1, PRMT1 and CARM1. The X-ray crystal structure of a DOT1L鈥搃nhibitor complex reveals that the N6-methyl group of the inhibitor, located favorably in a predominantly hydrophobic cavity of DOT1L, provides the observed high selectivity. Structural analysis shows that it will disrupt at least one H-bond and/or have steric repulsion for other histone methyltransferases. These compounds represent novel chemical probes for biological function studies of DOT1L in health and disease.