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
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 in suppressing the growth in cancer cells than the parent NSD2 binder. Moreover, compound was bioavailable in mice. Altogether, compound and its two controls and are valuable chemical tools for exploring the roles of NSD2 in health and disease.
