dGEM3

dGEM3 is a selective GEMIN3 Molecular glue degrader with a DC₅₀ of 680 nM. dGEM3 recruits GEMIN3 to the VHL E3 ligase, and mediates the targeted ubiquitination and degradation of GEMIN3 via the ubiquitin-proteasome system. dGEM3 induces extensive transcriptomic changes, including upregulation of ER stress response genes and downregulation of mRNA splicing genes. dGEM3 can be used in research related to amyotrophic lateral sclerosis, spinal muscular atrophy and neuromuscular dysfunction ^{[1] [2]}.

In Vitro, dGEM3 (0.001-100 μM; 2 h) binds to VHL in HEK293T cells with an IC₅₀ of 870 nM^[1]. dGEM3 (10 μM) selectively degrades GEMIN3 in a VHL-dependent manner in HEK293T, MV-4-11, MCF-7, JVM-3, and SH-SY5Y cells, with no degradation observed in VHL-deficient 786-O cells^[1]. dGEM3 (0.01-10 μM; 6-18 h) degrades GEMIN3 in HiBiT-GEMIN3 HEK293T cells with a DC₅₀ of 680 nM, reaching 75% maximal degradation at 18 h, via a VHL- and ubiquitin-proteasome system-dependent mechanism^[1]. dGEM3 selectively degrades the helicase GEMIN3 by acting as a molecular glue that bridges the canonical VHL E3 ligase pocket and GEMIN3’s ATP-binding lobe to form a productive ternary complex^[2]. dGEM3 (10 μM; 6 h) alters the transcriptome of HEK293T cells, with changes in ER stress response and mRNA splicing pathways^[1].

References:
[1]. Bushman J W, et al. Discovery of a VHL molecular glue degrader of GEMIN3 by Picowell RNA-seq[J]. bioRxiv, 2025: 2025.03. 19.644003.
[2]. Kozicka Z, et al. Clues for glues: from serendipity to nature's blueprints in degrader discovery. Essays in biochemistry. 2025 Dec 22;69(4):379-391.