DI-1859 (DI 1859) is a potent, selective and covalent DCN1 inhibitor with Ki of <1 nM, does not bind to DCN3, selectively inhibits neddylation of cullin 3 RING E3 ligase.
DI-1859 could inhibit cullin 3 neddylation at concentration as low as 1 nM, which is 1000 times more potent than DI-591.
DI-1859 selectively inhibits neddylation of cullin 3 in cells at low nanomolar concentrations and are 2-3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor DI-591.
DI-1859 at concentrations as low as 0.3 nM significantly reduced the level of neddylated cullin 3 and achieve profound inhibition of the neddylation of cullin 3 at 1-3 n.
DI-1859 is ~30 times more potent than MLN4924 in inhibition of the neddylation of cullin 3 in THLE2 liver cells.
DI-1859 induced a robust increase of NRF2 protein, a CRL3 substrate, in mouse liver and effectively protected mice from acetaminophen-induced liver damage.