Identification of a Novel Potent CYP4Z1 Inhibitor Attenuating the Stemness of Breast Cancer Cells through Lead Optimization

Pharmacological targeting cancer stem cells are emerging
as a novel
therapeutic modality for cancer treatment and prevention. Human cytochrome
P450 enzyme CYP4Z1 represents a promising target for its potential
role in attenuating the stemness of breast cancer cells. In order
to develop potent and selective CYP4Z1 inhibitors, a series of novel N-hydroxyphenylformamidines were rationally designed and
synthesized from a pan-CYP inhibitor HET0016. CYP4Z1 inhibitory activities
of the newly synthesized derivatives were evaluated, and the structure–activity
relationships (SARs) were summarized. Among them, compound 7c exhibited
the best inhibitory activity with an IC50 value of 41.8
nM. Furthermore, it was found that 7c decreased the expression
of stemness markers, spheroid formation, and metastatic ability as
well as tumor-initiation capability in a concentration-dependent manner
in vitro and in vivo. Altogether, compound 7c might be
a potential lead compound to develop CYP4Z1 inhibitor with more favorable
druggability for clinical application to treat breast cancer.