Recruitment of FBXO22 for targeted degradation of NSD2.

ABSTRACT: 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 a

SUBMITTER: Nie DY 

PROVIDER: S-EPMC11581931 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature