Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach
Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach
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DOI：
10.1021/acsmedchemlett.6b00167
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发表时间：
2016-08-01
影响因子：
4.2
通讯作者：
Gaul, Christoph
中科院分区：
文献类型：
--
作者：
Chen, Chao;Zhu, Hugh;Gaul, Christoph
致癌性MLL融合蛋白异常地将Dot1L（一种组蛋白甲基转移酶）募集到异位位点，导致H3K79的局部高甲基化和HoxA基因的错误表达，从而驱动MLL重排的白血病。在这种情况下，Dot1L的甲基转移酶活性的抑制预计会逆转异常的H3K79甲基化，导致白血病基因的抑制和肿瘤生长抑制。在我们的Dot1L药物发现计划的背景下，高通量筛选导致了2的鉴定，这是一种具有前所未有的诱导口袋结合模式的弱Dot1L抑制剂。一个药物化学运动，强烈引导基于结构的考虑和基于配体的变形，使12和13，有效的，选择性的，结构上完全新颖的Dot1L抑制剂的发现。
Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel Dot1L inhibitors.