WS-383 free base

WS-383 (WS383) is a highly potent, selective, and cellular active inhibitor of DCN1-UBC12 interaction with IC50 of 11 nM; inhibits Cul3/1 neddylation selectively over other cullins and also induces accumulation of p21, p27 and NRF2; exhibits cellular target engagement to DCN1 in MGC-803 cells, enhances the thermal stability of cellular DCN1 protein even at 1 uM

Research Areas >> Cancer

Signaling Pathways >> Metabolic Enzyme/Protease >> E1/E2/E3 Enzyme

IC50: 11 nM (DCN1–UBC12 interaction)[1]

WS-383 (10 μM) is against a panel of kinases such as BTK, CDKs, and EGFR [L858R] using staurosporine and afatinib as the positive controls. WS-383 showed weak inhibitory activity at 10.0 μM,it is selective to the DCN1–UBC12 interaction over the selected kinasesr[1]. WS-383 (0.03-3 μM;24 hours) blocks Cul3 neddylation at 3 μM and also has certain inhibition of Cul1 neddylation at 10 μM but was not effective in inhibiting neddylation of other cullin members[1]. WS-383 (0.03-3 μM;24 hours) increases Cul1, Skp1 (adaptor protein), F-box protein, and RBX1/RBX2 RING protein form SCF E3 complex. Cyclin dependent kinase inhibitor 1A (p21) and cyclin dependent kinase inhibitor 1B (p27) expression in a dose-dependent manner in MGC-803 and KYSE70 manner[1]. Western Blot Analysis[1] Cell Line: MGC-803 cells Concentration: 0.03 μM; 0.3 μM; 3 μM; 10 μM Incubation Time: 24 hours Result: Decreased N8-Cul1 and N8-Cul2 protein expression. Western Blot Analysis[1] Cell Line: MGC-803 and KYSE70 cells Concentration: 0.03 μM; 0.3 μM; 3 μM; 10 μM Incubation Time: 24 hours Result: Induced accumulation of p21, p27, and NRF2 in MGC-803 cells.

[1]. Wang S, et al. Development of Highly Potent, Selective, and Cellular Active Triazolo[1,5- a]pyrimidine-Based Inhibitors Targeting the DCN1-UBC12 Protein-Protein Interaction.J Med Chem. 2019 Mar 14;62(5):2772-2797.