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

J Med Chem. 2022-07; 
Fanye Meng, Chenxi Xu, Kwang-Su Park, H Ümit Kaniskan, Gang Greg Wang, Jian Jin
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Plasmid DNA Preparation … Construct of the NSD2-PWWP1 domain (residues 208–369) was cloned in pDEST15 vector from GenScript. The plasmid containing the NSD2-PWWP1 domain with N-terminal GST tag … Get A Quote


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, (MS159), and two structurally similar controls, (MS159N1) and (MS159N2), with diminished binding to the cereblon (CRBN) E3 ligase and NSD2, respectively. Compound , but not and , effectively degraded NSD2 in a concentration-, time-, CRBN-, and proteasome-dependent manner. Compound also effectively degraded CRBN neo-substrates IKZF1 and IKZF3, but not GSPT1. Importantly, compound was much more effective... More