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 in a covalent and reversible manner 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 highly potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a novel FBXO22-dependent TPD strategy.
Nuclear receptor-binding SET domain-containing 2 (NSD2) plays important roles in gene regulation, largely through its ability to dimethylate lysine 36 of histone 3 (H3K36me2). Despite aberrant activity of NSD2 reported in numerous cancers, efforts to selectively inhibit the catalytic activity of this protein with small molecules have been unsuccessful to date. Here, we report the development of UNC8153, a novel NSD2-targeted degrader that potently and selectively reduces the cellular levels of both NSD2 protein and the H3K36me2 chromatin mark. UNC8153 contains a simple warhead that confers proteasome-dependent degradation of NSD2 through a novel mechanism. Importantly, UNC8153-mediated reduction of H3K36me2 through the degradation of NSD2 results in the downregulation of pathological phenotypes in multiple myeloma cells including mild antiproliferative effects in MM1.S cells containing an activating point mutation and antiadhesive effects in KMS11 cells harboring the t(4;14) translocation that upregulates NSD2 expression.
Chromatin , Histones , Histones/metabolism , Gene Expression Regulation , Cell Line, Tumor , Down-Regulation
A new selenophosphoramide-catalyzed diamination of terminal- and trans-1,2-disubstituted olefins is presented. Key to the success of this transformation was the introduction of a fluoride scavenger, trimethylsilyl trifluoromethanesulfonate (TMSOTf), to prevent a competitive syn-elimination pathway, as was the use of a phosphoramide ligand on selenium to promote the desired substitution reaction. A screen of catalysts revealed that more electron-rich phosphine ligands resulted in higher yields of the desired product, with selenophosphoramides giving the optimal results. A broad range of substrates and functional groups were tolerated and yields were generally good to excellent. For (E)-1,2-disubstituted olefins, diastereoselectivities were always high, giving exclusively anti products. The conditions were also applied to substrates bearing internal nucleophiles such as esters and carbonates, giving rise to 1,2-aminoesters and cyclic carbonates, respectively.
Phosphine selenides are introduced as an alternate class of selenium-based catalysts for the aza-Heck reaction of alkenes. Using these catalysts, a range of terminal alkenes react with NFBS to give oxidative amination products. Judicious choice of phosphine ligand gives greater regio- and stereoselectivity than with diphenyl diselenide, enabling the selective formation of E terminal enimides in high yields. Isotope-labeling experiments and measurements of kinetic isotope effects reveal that the reaction occurs stereospecifically via irreversible anti addition, followed by rate-determining syn elimination.
