Department of Pharmacology, Baylor College of Medicine , 1 Baylor Plaza, Houston, Texas 77030, United States.
J Med Chem. 2013 Nov 27;56(22):8972-83. doi: 10.1021/jm4007752. Epub 2013 Aug 14.
Histone H3 lysine79 (H3K79) methyltransferase DOT1L plays an important role in the activation and maintenance of gene transcription. It is essential for embryonic development as well as normal functions of the hematopoietic system, heart, and kidney in adults. DOT1L has been found to be a drug target for acute leukemia with mixed lineage leukemia (MLL) gene translocations. The rearranged onco-MLL can recruit DOT1L, causing aberrant H3K79 methylation, overexpression of leukemia relevant genes, and eventually leukemogenesis. Potent DOT1L inhibitors possess selective activity against this type of leukemia in cell-based and animal studies, with the most advanced compound being in clinical trials. In the medicinal chemistry point of view, we review the biochemistry, cancer biology, and current inhibitors of DOT1L, as well as biophysical (including X-ray crystallographic) investigation of DOT1L-inhibitor interactions. Potential future directions in the context of drug discovery and development targeting DOT1L are discussed.
组蛋白 H3 赖氨酸 79（H3K79）甲基转移酶 DOT1L 在基因转录的激活和维持中发挥重要作用。它对于胚胎发育以及成人造血系统、心脏和肾脏的正常功能都是必不可少的。DOT1L 已被发现是具有混合谱系白血病（MLL）基因易位的急性白血病的药物靶点。重排的癌基因-MLL 可以募集 DOT1L，导致异常的 H3K79 甲基化、白血病相关基因的过表达，最终导致白血病发生。在细胞和动物研究中，具有选择性针对这种类型白血病的强效 DOT1L 抑制剂，其中最先进的化合物正在临床试验中。从药物化学的角度来看，我们综述了 DOT1L 的生物化学、癌症生物学和现有抑制剂，以及 DOT1L-抑制剂相互作用的生物物理（包括 X 射线晶体学）研究。讨论了针对 DOT1L 的药物发现和开发的潜在未来方向。
