Discovery of a First-in-Class Degrader for Nuclear Receptor Binding SET Domain Protein 2 (NSD2) and Ikaros/Aiolos

Overexpression of nuclear receptor binding SET domain protein 2 (NSD2) is frequent in multiple myeloma (MM). However, existing NSD2 inhibitors are largely ineffective in suppressing MM cell proliferation. Here, we report the discovery of a first-in-class NSD2 proteolysis targeting chimera (PROTAC) degrader, 9 (MS159), and two structurally similar controls, 17 (MS159N1) and 18 (MS159N2), with diminished binding to the cereblon (CRBN) E3 ligase and NSD2, respectively. Compound 9, but not 17 and 18, effectively degraded NSD2 in a concentration-, time-, CRBN-, and proteasome-dependent manner. Compound 9 also effectively degraded CRBN neo-substrates IKZF1 and IKZF3, but not GSPT1. Importantly, compound 9 was much more effective in suppressing the growth in cancer cells than the parent NSD2 binder. Moreover, compound 9 was bioavailable in mice. Altogether, compound 9 and its two controls 17 and 18 are valuable chemical tools for exploring the roles of NSD2 in health and disease.

核受体结合SET结构域蛋白2（nuclear receptor binding SET domain protein 2, NSD2）在多发性骨髓瘤（multiple myeloma, MM）中呈现高频过表达现象。然而，现有NSD2抑制剂在抑制MM细胞增殖方面效果普遍欠佳。本研究报道了一款首创的NSD2蛋白水解靶向嵌合体（proteolysis targeting chimera, PROTAC）降解剂9（MS159），以及两种结构相似的对照化合物17（MS159N1）与18（MS159N2），二者分别对cereblon（CRBN）E3连接酶和NSD2的结合能力显著减弱。化合物9（而非17和18）可通过浓度依赖性、时间依赖性、CRBN依赖性以及蛋白酶体依赖性的方式有效降解NSD2。化合物9还可有效降解CRBN新底物IKZF1与IKZF3，但无法降解GSPT1。尤为关键的是，化合物9在抑制癌细胞增殖方面的效果远优于其母核NSD2结合剂。此外，化合物9在小鼠体内具有生物利用度。综上，化合物9及其两种对照物17、18均可作为极具价值的化学工具，用于探究NSD2在健康与疾病状态下的生物学功能。