Nuclear receptor binding SET domain protein 2 (NSD2) is involved in various pathologic processes and is considered as an important target for cancer therapy. Due to alternative splicing, NSD2 has 3 isoforms: long, short and RE-IIBP. Although previous studies reported the degradation of PWWP1 domain-containing NSD2-long and short isoforms through PWWP1-binding molecules, the degradation of RE-IIBP which does not contain PWWP1 has been neglected to date. However, RE-IIBP plays an important role in cancer pathology, the further investigation of RE-IIBP requires novel chemical tools. Therefore, 31 novel SET domain ligand-based compounds bearing different E3 ligase ligands and amine moieties were synthesized and evaluated in this work. For the first time, the simultaneous degradation of NSD2-long and RE-IIBP isoforms was achieved through the primary alkylamine degrader ND-L11B. The degradation induced by ND-L11B led to the reduction of H3K36me2 level. Moreover, compared to the corresponding SET inhibitor, ND-L11B exhibited stronger antiproliferative activity on multiple myeloma cell line and negligible effect on non-malignant normal cell line. Whereas ND-L11B induced selective multiple myeloma cytotoxicity, it could serve as a starting point for the further development of NSD2-targeting therapies. This work provided a convenient chemical knockdown tool to further elucidate the multiple functions of NSD2 isoforms and expanded the applicability of alkyl primary amine analogs for targeted protein degradation.

中文翻译：

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发现 SET 结构域结合初级烷基胺栓系降解剂，用于同时降解 NSD2 长和 RE-IIBP 亚型


核受体结合 SET 结构域蛋白 2 （NSD2） 参与各种病理过程，被认为是癌症治疗的重要靶点。由于选择性剪接，NSD2 有 3 种亚型：长、短和 RE-IIBP。尽管以前的研究报道了通过 PWWP1 结合分子降解含有 PWWP1 结构域的 NSD2 长亚型和短亚型，但迄今为止，不含 PWWP1 的 RE-IIBP 的降解一直被忽视。然而，RE-IIBP 在癌症病理学中起着重要作用，RE-IIBP 的进一步研究需要新的化学工具。因此，本研究合成并评价了 31 种具有不同 E3 连接酶配体和胺基团的新型 SET 结构域配体化合物。首次通过初级烷基胺降解剂 ND-L11B 实现了 NSD2-long 和 RE-IIBP 亚型的同时降解。ND-L11B 诱导的降解导致 H3K36me2 水平降低。此外，与相应的 SET 抑制剂相比，ND-L11B 对多发性骨髓瘤细胞系表现出更强的抗增殖活性，而对非恶性正常细胞系的影响可以忽略不计。虽然 ND-L11B 诱导选择性多发性骨髓瘤细胞毒性，但它可以作为进一步开发 NSD2 靶向疗法的起点。这项工作提供了一种方便的化学敲低工具，以进一步阐明 NSD2 亚型的多种功能，并扩大了烷基伯胺类似物在靶向蛋白质降解中的适用性。