Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity.
Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity.
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DOI：
10.1038/s41467-021-23152-6
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发表时间：
2021-05-14
影响因子：
16.6
通讯作者：
Grembecka J
中科院分区：
文献类型：
--
作者：
Rogawski DS;Deng J;Li H;Miao H;Borkin D;Purohit T;Song J;Chase J;Li S;Ndoj J;Klossowski S;Kim E;Mao F;Zhou B;Ropa J;Krotoska MZ;Jin Z;Ernst P;Feng X;Huang G;Nishioka K;Kelly S;He M;Wen B;Sun D;Muntean A;Dou Y;Maillard I;Cierpicki T;Grembecka J
ASH1L 组蛋白甲基转移酶在包括急性白血病在内的不同疾病的发病机制中发挥着至关重要的作用。虽然 ASH1L 代表了一个有吸引力的药物靶点，但开发 ASH1L 抑制剂具有挑战性，因为催化 SET 结构域采用非活性构象，其自抑制环阻止了活性位点的进入。在这里，通过应用基于片段的筛选，然后进行药物化学和基于结构的设计，我们开发了 ASH1L SET 结构域的一流小分子抑制剂。 ASH1L 抑制剂复合物的晶体结构揭示了化合物与 SET 结构域中的自抑制环区域的结合。在 MLL 白血病模型中进行测试时，我们的先导化合物 AS-99 可以阻止细胞增殖，诱导细胞凋亡和分化，下调 MLL 融合靶基因，并减轻体内白血病负担。这项工作验证了 ASH1L SET 结构域作为可药物靶点的作用，并为进一步研究 ASH1L 的生物学功能以及开发治疗药物提供了化学探针。组蛋白甲基转移酶 ASH1L 在包括癌症在内的多种疾病中发挥作用，并已被验证为治疗靶点；然而，尚未报道 ASH1L 抑制剂。作者在此提出了 ASH1L 的小分子抑制剂，并证明了它们在白血病细胞和白血病小鼠模型中的靶向活性。
ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents. The histone methyltransferase ASH1L plays a role in various diseases, including cancer, and has been validated as a therapeutic target; however, no inhibitors of ASH1L have been reported. Here the authors present small molecule inhibitors of ASH1L and demonstrate their on-target activity in leukemia cells and a mouse model of leukemia.
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影响因子：
30.8
作者：
Armstrong, SA;Staunton, JE;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
1.6
作者：
DelProposto, James;Majmudar, Chinmay Y.;Brown, William Clay
通讯作者：
Brown, William Clay
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：
4
作者：
Fick, Robert J.;Kroner, Grace M.;Trievel, Raymond C.
通讯作者：
Trievel, Raymond C.