-methyladenosine (mA) methylation is the most abundant type of RNA modification that is mainly catalyzed by the METTL3-METTL14 methyltransferase complex. This complex has been linked to multiple cancers and is considered a promising therapeutic target for acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity were developed recently. Here, we present the discovery of WD6305 as the potent and selective proteolysis-targeting chimera (PROTAC) degrader of METTL3-METTL14 complex. WD6305 suppresses mA modification and the proliferation of AML cells, and promotes apoptosis much more effectively than its parent inhibitor. WD6305 also affects a variety of signaling pathways related to the development and proliferation of AML. Collectively, our study reveals PROTAC degradation of METTL3-METTL14 complex as a potential anti-leukemic strategy and provides desirable chemical tool for further understanding METTL3-METTL14 protein functions.

中文翻译：

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发现 METTL3-METTL14 复合物的 PROTAC 降解剂

-甲基腺苷 (mA) 甲基化是最丰富的 RNA 修饰类型，主要由 METTL3-METTL14 甲基转移酶复合物催化。该复合物与多种癌症有关，被认为是急性髓系白血病 (AML) 的有希望的治疗靶点。然而，最近仅开发了少数针对催化活性的 METTL3 抑制剂。在这里，我们发现了 WD6305 作为 METTL3-METTL14 复合物的有效、选择性蛋白水解靶向嵌合体 (PROTAC) 降解剂。WD6305 比其母体抑制剂更有效地抑制 m6A 修饰和 AML 细胞的增殖，并更有效地促进细胞凋亡。WD6305 还影响与 AML 发生和增殖相关的多种信号通路。总的来说，我们的研究揭示了 METTL3-METTL14 复合物的 PROTAC 降解作为一种潜在的抗白血病策略，并为进一步了解 METTL3-METTL14 蛋白功能提供了理想的化学工具。