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

Abstract

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.

There and Back Again: A Perspective on 20 Years of CYP4Z1

“…This 'suicide gene' strategy was further refined recently by Hanenberg's group for application in adoptive T-cell therapies using a highly active modified human CYP4B1 (Roellecke et al, 2016). Today, attention in this area has turned increasingly towards CYP4Z1 as the target for enzyme inhibitors (Kowalski et al, 2020 a ;Machalz et al, 2021;Yuan et al, 2022), and potentially as a protoxin activating CYP in breast cancer. There and back again indeed!…”

The roles of m6A RNA methylation modification in cancer stem cells: new opportunities for cancer suppression

“…Furthermore, CSCs have been found to have immunomodulatory activity as CSCs have been shown to exhibit the immunotherapeutic resistance. According to these characteristics, CSCs play an irreplaceable role in the treatment of malignant tumors as our previous studies have shown targeting CSCs can significantly suppress tumor migration, invasion, and drug resistance [32][33][34]. Epigenetics plays an important role in maintaining the above biological characteristics of CSCs, which refers to the phenomenon that the DNA sequence has not changed but the traits have heritable changes.…”