CDC20 binds to
anaphase-promoting complex/cyclosome E3 ubiquitin ligase to recruit substrates for ubiquitination to promote mitotic progression. In breast and other
cancers, CDC20 overexpression causes cell cycle dysregulation and is associated with poor prognosis.
Apcin was previously discovered as a CDC20 inhibitor exhibiting high micromolar activities. Here, we designed and developed new
apcin-based inhibitors by eliminating a
controlled substance,
chloral hydrate, required for synthesis. We further improved the antitumor activities of the inhibitors by replacing the
pyrimidine group with substituted
thiazole-containing groups. When evaluated in MDA-MB-231 and MDA-MB-468
triple negative breast cancer cell lines, several analogs showed 5-10-fold improvement over
apcin with IC50 values at ∼10 μM in cell viability assays.
Tubulin polymerization assay showed our CDC20 inhibitors had no off-target effects against
tubulin. Proapoptotic Bim accumulation was detected in our CDC20 inhibitor treated MDA-MB-468 cells. The most effective inhibitors, 22, warrant further development to target CDC20 in diseases.