Discovery of SET domain-binding primary alkylamine-tethered degraders for the simultaneous degradation of NSD2-long and RE-IIBP isoforms

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.