High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction.
High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction.
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DOI：
10.1021/ja306028q
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发表时间：
2013-01-16
影响因子：
15
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Karatas H;Townsend EC;Cao F;Chen Y;Bernard D;Liu L;Lei M;Dou Y;Wang S
混合谱系白血病1（MLL 1）是组蛋白H3赖氨酸4（H3 K4）甲基转移酶，靶向MLL 1酶活性已被提出作为治疗携带MLL 1融合蛋白的急性白血病的新治疗策略。MLL 1/WDR 5蛋白-蛋白相互作用对于MLL 1酶活性是必不可少的。在本研究中，我们设计了大量的肽模拟物，以靶向MLL 1/WDR 5相互作用的基础上-CO-ARA-NH-，最小的结合基序来自MLL 1。我们的研究导致了高亲和力肽模拟物的设计，其以Ki < 1 nM结合WDR 5，并在完全重构的体外H3 K4甲基转移酶测定中作为MLL 1活性的有效拮抗剂发挥作用。与WDR 5复合的两种有效肽模拟物的共晶体结构的测定建立了它们与WDR 5高亲和力结合的结构基础。在用MLL 1-AF 9融合构建体转导的骨髓细胞中对一种这样的肽模拟物MM-102的评价显示，该化合物有效地降低了MLL 1融合蛋白介导的白血病发生中的两个关键MLL 1靶基因HoxA 9和Meis-1的表达。MM-102还特异性抑制细胞生长并诱导携带MLL 1融合蛋白的白血病细胞凋亡。我们的研究为设计WDR 5/MLL 1蛋白质-蛋白质相互作用的小分子抑制剂作为携带MLL 1融合蛋白的急性白血病的新型治疗方法提供了第一个概念验证。
Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase, and targeting the MLL1 enzymatic activity has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. The MLL1/WDR5 protein–protein interaction is essential for MLL1 enzymatic activity. In the present study, we designed a large number of peptidomimetics to target the MLL1/WDR5 interaction based upon –CO-ARA-NH–, the minimum binding motif derived from MLL1. Our study led to the design of high-affinity peptidomimetics, which bind to WDR5 with Ki < 1 nM and function as potent antagonists of MLL1 activity in a fully reconstituted in vitro H3K4 methyltransferase assay. Determination of co-crystal structures of two potent peptidomimetics in complex with WDR5 establishes their structural basis for high-affinity binding to WDR5. Evaluation of one such peptidomimetic, MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows that the compound effectively decreases the expression of HoxA9 and Meis-1, two critical MLL1 target genes in MLL1 fusion protein mediated leukemogenesis. MM-102 also specifically inhibits cell growth and induces apoptosis in leukemia cells harboring MLL1 fusion proteins. Our study provides the first proof-of-concept for the design of small-molecule inhibitors of the WDR5/MLL1 protein–protein interaction as a novel therapeutic approach for acute leukemia harboring MLL1 fusion proteins.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
20.3
作者：
Faber, Joerg;Krivtsov, Andrei V.;Armstrong, Scott A.
通讯作者：
Armstrong, Scott A.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
23.9
作者：
Li, Xiangzhi;Li, Li;Pandey, Ruchi;Byun, Jung S.;Gardner, Kevin;Qin, Zhaohui;Dou, Yali
通讯作者：
Dou, Yali
影响因子：
64.5
作者：
Dou, YL;Milne, TA;Roeder, RG
通讯作者：
Roeder, RG