Proteolytic targeting chimera (PROTAC) is a heterobifunctional small molecule, including two active domains, and a linker. Importantly, it can remove specific unwanted proteins. PROTAC is a technology based on the ligand binding of TAP and then the degradation of TAP. PROTAC provides an alternative approach to those so-called non-druggable targets, such as transcription factors.

Obviously, The methyltransferase nuclear receptor SET domain 2 (NSD2) is a member of the NSD protein lysine methyltransferase (KMT) family. It can cause epigenome abnormalities by changing methylation status. Particularly, NSD2 is frequently overexpressed in a variety of aggressive solid tumors. This upregulation is relevant to poor prognosis and recurrence. Overexpression of NSD2 promotes cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), indicating its potential carcinogenic role in solid tumors. Specifically, NSD2 is relevant to H4K20 methylation at DNA double-strand breaks (DSBs) and recruitment of 53BP1 to DNA damage sites. Here, we will introduce a first-In-class NSD2 PROTAC degrader for multiple myeloma research, MS159.

MS159 is a First-In-class NSD2 PROTAC degrader for Multiple Myeloma Research.

Above all, MS159 is a potent nuclear receptor binding SET structural domain protein 2 (NSD2) PROTAC degrader. Besides, MS159 inhibits the growth of tumor cells. Meanwhile, MS159 is a useful chemical tool for exploring the role of NSD2 in health and disease.

Next in importance, MS159 can induce the degradation of NSD2 protein in a time- and dose-dependent manner. However, the induced NSD2 degradation is reversible in 293FT cells. Nonetheless, MS159 can effectively degrade NSD2 as well as IKZF1 and IKZF3 in multiple myeloma cell lines KMS11 and H929. Additionally, the degradation of IKZF1/3 is mediated through a ubiquitin-proteasome system (UPS-) and carbon (CRBN-) dependent mechanism. Moreover, MS159 can effectively inhibit the growth of KMS11 and H929 multiple myeloma cells through induced NSD2 degradation.

All in all, MS159 is a first-In-class NSD2 PROTAC degrader for multiple myeloma research.


Fanye Meng, et al. J Med Chem. 2022 Aug 11;65(15):10611-10625.