HGC652

HGC652 is a molecular glue degrader targeting TRIM21 with a TRIM21-dependent nuclear membrane disruption effect. HGC652 binds to the PRY-SPRY domain of TRIM21 with high affinity ( K a =0.061 μM), mediates the interaction between TRIM21 and NUP98, and redirects E3 ligase activity. By triggering the polyubiquitination and proteasomal degradation of nucleoporins (such as NUP155 and GLE1 ), HGC652 disrupts nuclear membrane integrity, alters nuclear morphology, induces genomic instability, and thereby induces cancer cell death ^{[1] [2]}.

In Vitro, The IC₅₀ of HGC652 for inhibiting the proliferation of PANC-1 pancreatic cancer cells is 0.094 μM (72 h)^[1]. HGC652 (0.5-5 μM; 24 h) induces dose-dependent degradation of GLE1 and NUP155 in PANC-1 cells via a proteasome-dependent pathway^[1]. HGC652 (0.05-5 μM; 24 h incubation) induces NUP155 degradation in PANC-1 cells, and this process is independent of GLE1; whereas the degradation of GLE1 depends on NUP155, indicating that NUP155 is its primary target^[1]. HGC652 (0.01-25 μM; room temperature; 40 min) induces the formation of a concentration-dependent ternary complex between TRIM21PRY-SPRY and NUP98APD proteins^[1]. HGC652 (0.5-15 μM; incubated on ice; 30 min; incubated with streptavidin agarose beads for 2 h) induces direct interaction between TRIM21 (124-475) and NUP98APD in cell-free Strep-tag pull-down assays^[2].

References:
[1]. Li X, et al. Chemically Induced Nuclear Pore Complex Protein Degradation via TRIM21. ACS Chem Biol. 2025 May 16;20(5):1020-1028.
[2]. Cheng Y, et al. TRIM21-NUP98 Interface Accommodates Structurally Diverse Molecular Glue Degraders. ACS Chem Biol. 2025 Apr 18;20(4):953-959.