Discovery of a Potent and Selective Targeted NSD2 Degrader for the Reduction of H3K36me2

Abstract

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.

A conserved role of hnRNPL in regulating alternative splicing of transcriptional regulators necessary for B cell activation

“…Given the association of H3K36me2 with transcription regulation (Lam et al , 2022), it would likely impinge on gene expression too. NSD2 deficiency reduces H3K36me2 but also H3K36me3 (Dobenecker et al , 2020; Hanley et al , 2023) and hnRNPL depletion also reduces H3K36me3 levels and transcription in cell lines (Yuan et al , 2009b; Huang et al , 2012), which could be partly regulated by its effect on NSD2 splicing. Interestingly, hnRNPL is a cofactor of SETD2, the methyltransferase catalyzing H3K36me3 onto H3K36me2.…”

Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

“…Type 1 N-degrons contain basic residues, including Arg, Lys, and His. In 2023, inspired by this novel approach of using N-degron as a UBR E3 ligase recruiting ligand, a series of 14 (UNC6934)-based heterobifunctional molecules were designed by replacing the terminal pyrimidine ring of 14 that extends into the solvent exposure region with a phenyl ring . Simultaneously, an Arg or His was tethered to the para-position of benzene through alkyl amine linkers with different lengths.…”

“…In 2023, inspired by this novel approach of using N-degron as a UBR E3 ligase recruiting ligand, 268 a series of 14 (UNC6934)based heterobifunctional molecules were designed by replacing the terminal pyrimidine ring of 14 that extends into the solvent exposure region with a phenyl ring. 269 Simultaneously, an Arg or His was tethered to the para-position of benzene through alkyl amine linkers with different lengths. Such a design with eight new compounds containing Arg and His was anticipated to induce the degradation of NSD2 through recruiting a UBR E3 ligase into proximity with NSD2.…”

Discovery of LLC0424 as a Potent and Selective in Vivo NSD2 PROTAC Degrader

“…Moreover, the global proteomics selectivity and the in vivo NSD2 degradative effects of compound 6 have not been evaluated. In 2023, Lindsey and co-workers discovered a new NSD2 degrader UNC8153 ( 7 ) that depleted NSD2 through a novel mechanism . Compound 7 degraded NSD2 with a DC 50 value of 0.35 μM and a D max value of 79% in U2OS cells after 24 h treatment and exhibited high selectivity in global proteomics experiments.…”