Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Nat Commun. 2021 May 14;12(1):2792. doi: 10.1038/s41467-021-23152-6.
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.
ASH1L 组蛋白甲基转移酶在包括急性白血病在内的多种疾病的发病机制中起着至关重要的作用。虽然 ASH1L 是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 结构域适应无活性构象，自动抑制环阻止其进入活性部位。在这里，我们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，开发了一类新型的 ASH1L SET 结构域小分子抑制剂。ASH1L-抑制剂复合物的晶体结构揭示了化合物结合到 SET 结构域中的自动抑制环区域。当在 MLL 白血病模型中进行测试时，我们的先导化合物 AS-99 可阻断细胞增殖，诱导细胞凋亡和分化，下调 MLL 融合靶基因，并减少体内白血病负担。这项工作验证了 ASH1L SET 结构域作为可成药的靶标，并提供了一个化学探针，以进一步研究 ASH1L 的生物学功能，并开发治疗剂。
