小柯机器人

英国剑桥大学Tony Kouzarides等研究人员合作发现，METTL3的小分子抑制可作为髓样白血病的治疗策略。该项研究成果于2021年4月26日在线发表在《自然》杂志上。

研究人员表示，N6-甲基腺苷（m⁶A）是一种主要由METTL3–METTL14甲基转移酶复合物催化的RNA修饰。m⁶A的修饰蛋白METTL3与急性髓细胞性白血病（AML）的发生和维持有关，但其真正的治疗重要性仍未知。

研究人员报道了METTL3的高效、选择性的首个催化抑制剂（STM2457）及其与METTL3/METTL14结合的共晶体结构的鉴定和表征。STM2457的治疗可导致AML的生长减少，并促进分化和凋亡。这些细胞作用伴随着已知白血病生成mRNA上m⁶A水平的选择性降低以及与翻译缺陷一致的表达降低。研究人员证明了METTL3在体内的药理学抑制导致移植受损和各种AML小鼠模型中的生存期延长，特别是针对AML的关键干细胞亚群。

总的来说，这些结果揭示了对METTL3的抑制可作为一种潜在的针对AML的治疗策略，并提供了概念性证明，即靶向RNA修饰酶是抗癌治疗的潜在新途径。

附：英文原文

Title: Small molecule inhibition of METTL3 as a strategy against myeloid leukaemia

Author: Eliza Yankova, Wesley Blackaby, Mark Albertella, Justyna Rak, Etienne De Braekeleer, Georgia Tsagkogeorga, Ewa S. Pilka, Demetrios Aspris, Dan Leggate, Alan G. Hendrick, Natalie A. Webster, Byron Andrews, Richard Fosbeary, Patrick Guest, Nerea Irigoyen, Maria Eleftheriou, Malgorzata Gozdecka, Joao M. L. Dias, Andrew J. Bannister, Binje Vick, Irmela Jeremias, George S. Vassiliou, Oliver Rausch, Konstantinos Tzelepis, Tony Kouzarides

Issue&Volume: 2021-04-26

Abstract: The N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 catalysed predominantly by the METTL3–METTL14 methyltransferase complex3,4. The m6A writer METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but its true therapeutic importance is still unknown5–7. Here we present the identification and characterization of a highly potent and selective first-in-class catalytic inhibitor of METTL3 (STM2457) and its co-crystal structure bound to METTL3/METTL14. Treatment with STM2457 leads to reduced AML growth, and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various AML mouse models, specifically targeting key stem-cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA modifying enzymes represents a promising new avenue for anti-cancer therapy.

DOI: 10.1038/s41586-021-03536-w

Source: https://www.nature.com/articles/s41586-021-03536-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html