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.