High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity
High-affinity small molecular blockers of mixed lineage leukemia 1 (MLL1)-WDR5 interaction inhibit MLL1 complex H3K4 methyltransferase activity
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混合谱系白血病 1 (MLL1)-WDR5 相互作用的高亲和力小分子阻断剂抑制 MLL1 复合物 H3K4 甲基转移酶活性
DOI：
10.1016/j.ejmech.2016.08.036
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发表时间：
2016-11-29
影响因子：
6.7
通讯作者：
Guo, Xiao-Ke
中科院分区：
文献类型：
--
作者：
Li, Dong-Dong;Chen, Wei-Lin;Guo, Xiao-Ke
MLL 1-WDR 5蛋白-蛋白相互作用对于MLL 1 H3 K4甲基转移酶活性是必需的。靶向MLL 1酶活性以调节MLL依赖性基因的表达水平代表了携带MLL融合蛋白的急性白血病的治疗策略。本文报道了一系列干扰MLL 1-WDR 5相互作用的联苯类化合物。这些化合物在体外和MV 4 -11细胞系中有效地抑制MLL 1组蛋白甲基转移酶（HMT）活性。代表性化合物30（DDO-2084）通过下调Hoxa 9和Meis-1基因的表达水平来抑制MV 4 -11细胞的增殖并诱导细胞凋亡，这强调了我们的化合物是靶向的。化合物30的优化导致高亲和力抑制剂。特别是，带有氨基和4-氨基丁酰胺基的化合物42（DDO-2117，IC 50 = 7.6 nM）是迄今报道的最有效的抑制剂，并且在HMT测定中显示出最有效的抑制活性（IC 50 = 0.19 μ M）。(C)2016年Elsevier Masson SAS。All rights reserved.
MLL1-WDR5 protein-protein interaction is essential for MLL1 H3K4 methyltransferase activity. Targeting MLL1 enzymatic activity to regulate expression level of MLL-dependent genes represents a therapeutic strategy for acute leukemia harboring MLL fusion proteins. Herein we reported a series of biphenyl compounds disturbed MLL1-WDR5 interaction. These compounds effectively inhibited MLL1 histone methyltransferase (HMT) activity in vitro and in MV4-11 cell line. The representative compound 30 (DDO-2084) inhibited proliferation and induced apoptosis of MV4-11 cells through deregulating expression level of Hoxa9 and Meis-1 genes, which emphasized our compounds were on-target. Optimization of compound 30 led to high-affinity inhibitors. Especially, compound 42 (DDO-2117, IC50 = 7.6 nM) bearing an amino and a 4-aminobutanamido group was the most potent inhibitor reported to-date, and showed the most potent inhibitory activity (IC50 = 0.19 mu M) in HMT assay. (C) 2016 Elsevier Masson SAS. All rights reserved.