Nuclear receptor-binding SET domain-containing 2 (NSD2), a methyltransferase that primarily installs the dimethyl mark on lysine 36 of histone 3 (H3K36me2), has been recognized as a promising therapeutic target against cancer. However, existing NSD2 inhibitors suffer from low activity or inferior selectivity, and none of them can simultaneously remove the methyltransferase activity and chromatin binding function of NSD2. Herein we report the discovery of a novel NSD2 degrader LLC0424 by leveraging the proteolysis-targeting chimera technology. LLC0424 potently degraded NSD2 protein with a DC₅₀ value of 20 nM and a D_max value of 96% in acute lymphoblastic leukemia (ALL) RPMI-8402 cells. Mechanistic studies revealed LLC0424 to selectively induce NSD2 degradation in a cereblon- and proteasome-dependent fashion. LLC0424 also caused continuous downregulation of H3K36me2 and growth inhibition of ALL cell lines with NSD2 mutation. Importantly, intravenous or intraperitoneal injection of LLC0424 showed potent NSD2 degradation in vivo.

中文翻译：

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发现 LLC0424 作为体内 NSD2 PROTAC 有效且选择性的降解剂

核受体结合 SET 结构域 2 (NSD2) 是一种甲基转移酶，主要在组蛋白 3 (H3K36me2) 的赖氨酸 36 上安装二甲基标记，已被认为是一种有前景的癌症治疗靶点。然而，现有的NSD2抑制剂活性低或选择性差，且均不能同时消除NSD2的甲基转移酶活性和染色质结合功能。在此，我们报告利用蛋白水解靶向嵌合体技术发现了一种新型 NSD2 降解剂LLC0424 。 LLC0424可有效降解急性淋巴细胞白血病 (ALL) RPMI-8402 细胞中的NSD2 蛋白，DC ₅₀值为 20 nM，D _max值为 96%。机理研究表明LLC0424以 cereblon 和蛋白酶体依赖性方式选择性诱导 NSD2 降解。LLC0424还引起 H3K36me2 的持续下调和 NSD2 突变的 ALL 细胞系的生长抑制。重要的是，静脉内或腹膜内注射LLC0424显示出体内NSD2 的有效降解。