2. Academic Validation
  3. Identification of a Novel Potent CYP4Z1 Inhibitor Attenuating the Stemness of Breast Cancer Cells through Lead Optimization

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

  • J Med Chem. 2022 Dec 8;65(23):15749-15769. doi: 10.1021/acs.jmedchem.2c01320.
Yin Yuan 1,  Hong Yao 2,  Manzhen Zhou 2,  Xiaoqian Ma 2,  Yi Zhou 1,  Jinyi Xu 2,  Miaomiao Niu 3,  Jun Yin 1,  Lufeng Zheng 1,  Shengtao Xu 2 4
Affiliations

Affiliations

  • 1 School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China.
  • 2 Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China.
  • 3 Key Laboratory of Drug Quality Control and Pharmacovigilance, Jiangsu Key Laboratory of Drug Design and Optimization, Ministry of Education, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China.
  • 4 Department of Hepatobiliary Surgery, The First People's Hospital of Kunshan, Suzhou 215132, P. R. China.
PMID: 36414390 DOI: 10.1021/acs.jmedchem.2c01320
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.

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