Discovery of NSD2-Degraders from Novel and Selective DEL Hits

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• NSD2 (Nuclear Receptor Binding Set Domain Containing Protein 2) is a histone methyltransferase.
• Aberrant NSD2 activity, driven by mutations or translocations like t(4;14), is oncogenic and implicated in cancers such as multiple myeloma and acute lymphoblastic leukemia.
• Specifically, the NSD2 E1099K mutant exhibits hyperactive methyltransferase function.

Purpose of the Study:

• To identify and develop novel small molecules targeting NSD2.
• To investigate the therapeutic potential of NSD2 degradation in cancer treatment.
• To explore the impact of NSD2 inhibition on histone methylation and cancer cell proliferation.

Main Methods:

• Utilized DNA-encoded libraries to discover small molecule ligands binding to the NSD2 PWWP1 domain.
• Developed selective VHL1-recruiting degraders based on identified ligands.
• Assessed the efficacy of NSD2 degraders in cancer cell lines, measuring NSD2 degradation, H3K36me2 levels, and cell proliferation.

Main Results:

• Identified potent and selective small molecule ligands that bind to the NSD2 PWWP1 domain.
• These ligands inhibit NSD2's interaction with H3K36me2-nucleosomes without affecting its methyltransferase activity.
• Developed effective NSD2 degraders that induce protein degradation, decrease H3K36me2 levels, and inhibit cancer cell proliferation.

Conclusions:

• Small molecule ligands targeting the NSD2 PWWP1 domain offer a novel therapeutic strategy.
• Targeted degradation of NSD2 is a viable approach for treating NSD2-driven cancers.
• Inhibition of NSD2 activity through degradation reduces oncogenic histone methylation and suppresses tumor cell growth.