Figure 1: CSN5i-3 is a potent inhibitor of CSN5-catalysed cullin deneddylation.
From: Targeted inhibition of the COP9 signalosome for treatment of cancer
(a) Schematic illustration of the CRL cycle and the role of cullin neddylation and deneddylation. Ad, adaptor protein; SRM, interchangeable substrate recognition module; Sub, substrate. (b) Chemical structures of CSN5 inhibitors illustrating the optimization of the high throughput screening (HTS) hit CSN5i-1a to the cell active intermediate CSN5i-2, its R,R-enantiomer CSN5i-2e and to the final compound CSN5i-3. (c) Co-crystal structures of CSN5 with CSN5i-1b and CSN5i-3. The structures revealed the direction for compound extension into the substrate binding cleft of CSN5 (red arrow). (d) Dose–response curve for inhibition of CSN activity by CSN5i-3 as measured in a biochemical enzyme assay (n=2, ±s.d.). (e) Immunoblotting for Cul1 after treatment of HCT116 cells with 1 μM CSN5i-3 and for Cul1 and CSN5 after treatment with CSN5 siRNA.
