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N 6-methyladenosine (m6A) 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 m6A 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. [Display omitted] • WD6305, a potent METTL3-targeted PROTAC degrader, is developed • WD6305 selectively reduces the METTL3 and METTL14 complex • METTL3 degradation outperforms METTL3 inhibition in AML antiproliferation Du et al. discovered and characterized WD6305, a selective METTL3-targeted PROTAC. This compound effectively and selectively abolishes the METTL3 and METT14 complex. Their findings demonstrate that pharmacological degradation of METTL3-METTL14 complex surpasses its inhibition as a potential anti-leukemic strategy. [ABSTRACT FROM AUTHOR]

Nuclear receptor binding SET domain protein 3 (NSD3) is an attractive potential target in the therapy for human cancers. Herein, we report the discovery of a series of small-molecule NSD3 degraders based on the proteolysis targeting chimera (PROTAC) strategy. The represented compound 8 induces NSD3 degradation with DC 50 values of 1.43 and 0.94 μM in NCI–H1703 and A549 lung cancer cells, respectively, and shows selectivity over two other NSD proteins. 8 reduces histone H3 lysine 36 methylation and induces apoptosis and cell cycle arrest in lung cancer cells. Moreover, the RNA sequencing and immunohistochemistry assays showed that 8 downregulates NSD3-associated gene expression. Significantly, 8 , but not 1 (a reported NSD3-PWWP antagonist) could inhibit the cell growth of NCI–H1703 and A549 cells. A single administration of 8 effectively decreases the NSD3 protein level in lung cancer xenograft models. Therefore, this study demonstrated that inducing NSD3 degradation is a more effective approach inhibiting the function of NSD3 than blocking the NSD3-PWWP domain, which may provide a potential therapeutic approach for lung cancer. [Display omitted] • A potent and selective PROTAC degrader of NSD3 was designed, synthesized and evaluated. • Compound 8 decreased NSD3-associated genes and H3K36me3. • Compound 8 induced lung cancer cell growth arrest and apoptosis. • Compound 8 inhibited proliferation and clone formation in lung cancer cells. • A single dose of compound 8 effectively reduced NSD3 in xenograft tumor tissue in mice. [ABSTRACT FROM AUTHOR]