Journal Article

Recruitment of FBXO22 for targeted degradation of NSD2

Brown, Nicholas G., Menes, Michael, Barsyte-Lovejoy, Dalia, Li, Jianping, Licht, Jonathan D., St-Germain, Jonathan, Paulakonis, Ethan, Stamford, Andrew W., Duan, Shili, Lamberto, Anthony Joseph, Nie, David Y., Raught, Brian, James, Lindsey I., Hanley, Ronan P., Kenney, Tristan M. G., Wolf, Esther, Owens, Dominic D. G., Szewczyk, Magdalena, Maitland, Matthew E. R., Shrestha, Suman, Kutera, Maria, Li, Fengling, Tabor, John R., Barsotti, Anthony M., Collins, Jon L., Arrowsmith, Cheryl H., Pon, Ailing, Penn, Linda Z., Wilson, Derek J.

2024

Overview

Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain-of-function mutation p.E1099K, resulting in growth suppression, apoptosis and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 to recruit the SCF FBXO22 Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCF FBXO22 . Overall, we present a potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a new FBXO22-recruitment strategy for TPD. Nie et al. describe a mechanism underlying the degradation of the histone methyltransferase NSD2 through the recruitment of FBXO22 E3 ligase, providing a chemical probe for NSD2 function study and targeted protein degradation.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/1059 / 631/92/609 / 631/92/613 / 631/92/96 / Acute lymphoblastic leukemia / Aldehydes / Apoptosis / Apoptosis - drug effects / Biochemical Engineering / Biochemistry / Biodegradation / Biology / Bioorganic Chemistry / Cell Biology / Cell Line, Tumor / Chemistry / Chemistry and Materials Science / Chemistry/Food Science / Cullin / Degradation / Drug resistance / F-Box Proteins - genetics / F-Box Proteins - metabolism / Histone methyltransferase / Histone-Lysine N-Methyltransferase - genetics / Histone-Lysine N-Methyltransferase - metabolism / Histones / Humans / Leukemia / Ligands / Lymphatic leukemia / Multiple myeloma / Phenotypes / Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy / Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics / Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism / Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology / Proteasomes / Proteins / Proteolysis - drug effects / Receptors, Cytoplasmic and Nuclear / Repressor Proteins - genetics / Repressor Proteins - metabolism / Specialty products / Ubiquitin-protein ligase / XIAP protein