Author:
Nie David Y.,Tabor John R.,Li Jianping,Kutera Maria,St-Germain Jonathan,Hanley Ronan P.,Wolf Esther,Paulakonis Ethan,Kenney Tristan M.G.,Duan Shili,Shrestha Suman,Owens Dominic D.G.,Pon Ailing,Szewczyk Magdalena,Lamberto Anthony Joseph,Menes Michael,Li Fengling,Barsyte-Lovejoy Dalia,Brown Nicholas G.,Barsotti Anthony M.,Stamford Andrew W.,Collins Jon L.,Wilson Derek J.,Raught Brian,Licht Jonathan D.,James Lindsey I.,Arrowsmith Cheryl H.
Abstract
AbstractTargeted 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 in a covalent and reversible manner to recruit the SCFFBXO22Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCFFBXO22. Overall, we present a highly potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a novel FBXO22-dependent TPD strategy.
Publisher
Cold Spring Harbor Laboratory