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

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Identification of a Novel Potent CYP4Z1 Inhibitor Attenuating the Stemness of Breast Cancer Cells through Lead Optimization
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-22 , 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,

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Affiliation

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.

中文翻译：

鉴定一种新型强效 CYP4Z1 抑制剂，通过先导优化减弱乳腺癌细胞的干性

靶向癌症干细胞的药理学正在成为癌症治疗和预防的新型治疗方式。人细胞色素 P450 酶 CYP4Z1 代表了一个有前途的目标，因为它在减弱乳腺癌细胞的干性方面具有潜在作用。为了开发有效和选择性的 CYP4Z1 抑制剂，以泛 CYP 抑制剂 HET0016 为原料，合理设计并合成了一系列新型N-羟基苯基甲脒。评估了新合成衍生物的 CYP4Z1 抑制活性，并总结了构效关系 (SAR)。其中，化合物7c表现出最好的抑制活性，IC ₅₀值为41.8 nM。此外，还发现7c在体外和体内以浓度依赖性方式降低干细胞标记物的表达、球体形成和转移能力以及肿瘤起始能力。总而言之，化合物7c可能是开发 CYP4Z1 抑制剂的潜在先导化合物，具有更有利的成药性，可用于治疗乳腺癌的临床应用。

更新日期：2022-11-22

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