Exploring Marine-Derived Ascochlorins as Novel Human Dihydroorotate Dehydrogenase Inhibitors for Treatment of Triple-Negative Breast Cancer

Human
dihydroorotate dehydrogenase (hDHODH) is
an attractive tumor target essential to de novo pyrimidine biosynthesis.
Novel potent hDHODH inhibitors with low toxicity
are urgently needed. Herein, we demonstrate the isolation of 25 ascochlorin
(ASC) derivatives, including 13 new ones, from the coral-derived fungus Acremonium sclerotigenum, and several of them showed
pronounced inhibitions against hDHODH and triple-negative
breast cancer (TNBC) cell lines, MDA-MB-231/-468. Interestingly, we
found that hDHODH is required for proliferation and
survival of TNBC cells, and several ASCs significantly inhibited TNBC
cell growth and induced their apoptosis via hDHODH
inhibition. Furthermore, the novel and potent hDHODH
inhibitors (1 and 21) efficiently suppressed
tumor growth in patient-derived TNBC xenograft models without obvious
body weight loss or overt toxicity in mice. Collectively, our findings
offered a novel lead scaffold as the hDHODH inhibitor
for further development of potent anticancer agents and a potential
therapeutic strategy for TNBC.