Nuclear receptor binding SET domain protein 3 (NSD3), a gene located within the 8p11-p12 amplicon frequently detected in human cancers, encodes a chromatin modulator and an attractive onco-target. However, agents that effectively suppress NSD3-mediated oncogenic actions are currently lacking. We report the NSD3-targeting proteolysis targeting chimera (PROTAC), MS9715, which achieves effective and specific targeting of NSD3 and associated cMyc node in tumor cells. MS9715 is designed by linking BI-9321, a NSD3 antagonist, which binds NSD3’s PWWP1 domain, with an E3 ligase VHL ligand. Importantly, MS9715, but not BI-9321, effectively suppresses growth of NSD3-dependent hematological cancer cells. Transcriptomic profiling demonstrates that MS9715, but not BI-9321, effectively suppresses NSD3-and cMyc-associated gene expression programs, resembling effects of the CRISPR-Cas9-mediated knockout of NSD3. Collectively, these results suggest that pharmacological degradation of NSD3 as an attractive therapeutic strategy, which co-suppresses NSD3- and cMyc-related oncogenic nodes, is superior to blocking the PWWP1 domain of NSD3.

核受体结合 SET 结构域蛋白 3 (NSD3) 是一种位于人类癌症中经常检测到的 8p11-p12 扩增子内的基因，它编码染色质调节剂和有吸引力的致癌靶标。然而，目前缺乏有效抑制 NSD3 介导的致癌作用的药物。我们报告了 NSD3 靶向蛋白水解靶向嵌合体 (PROTAC)，MS9715，它实现了肿瘤细胞中 NSD3 和相关 cMyc 节点的有效和特异性靶向。MS9715 是通过将结合 NSD3 的 PWWP1 结构域的 NSD3 拮抗剂 BI-9321 与 E3 连接酶 VHL 配体连接而设计的。重要的是，MS9715，而非 BI-9321，能有效抑制 NSD3 依赖性血液癌细胞的生长。转录组学分析表明，MS9715（而非 BI-9321）有效抑制 NSD3 和 cMyc 相关基因表达程序，类似于 CRISPR-Cas9 介导的 NSD3 敲除的效果。总的来说，这些结果表明，NSD3 的药理学降解作为一种有吸引力的治疗策略，可以共同抑制 NSD3 和 cMyc 相关的致癌节点，优于阻断 NSD3 的 PWWP1 结构域。