Discovery of Potent and Selective 2‑(Benzylthio)pyrimidine-based DCN1-UBC12 Inhibitors for Anticardiac Fibrotic Effects

DCN1,
a co-E3 ligase, interacts with UBC12 and activates cullin–RING
ligases (CRLs) by catalyzing cullin neddylation. Although DCN1 has
been recognized as an important therapeutic target for human diseases,
its role in the cardiovascular area remains unknown. Here, we first
found that DCN1 was upregulated in isolated cardiac fibroblasts (CFs)
treated by angiotensin (Ang) II and in mouse hearts after pressure
overload. Then, structure-based optimizations for DCN1-UBC12 inhibitors
were performed based on our previous work, yielding compound DN-2. DN-2 specifically targeted DCN1 at molecular
and cellular levels as shown by molecular modeling studies, HTRF,
cellular thermal shift and co-immunoprecipitation assays. Importantly, DN-2 effectively reversed Ang II-induced cardiac fibroblast
activation, which was associated with the inhibition of cullin 3 neddylation.
Our findings indicate a potentially unrecognized role of DCN1 inhibition
for anticardiac fibrotic effects. DN-2 may be used as
a lead compound for further development.