Design and Characterization of the First Selective and Potent Mechanism-Based Inhibitor of Cytochrome P450 4Z1

Kowalski, John P.; McDonald, Matthew; Pelletier, Robert; Wiek, Constanze; Rettie, Allan E.

doi:10.1021/acs.jmedchem.0c00101

Cited by 17 publications

(27 citation statements)

References 53 publications

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“…Knowledge in the field of the CYP4Z1 enzyme’s substrate recognition and catalytic properties is now quite valuable in the design and development of more selective cancer therapies. A limited number of reports explored the substrate-binding mode of CYP4Z1 [ 35 , 36 , 37 , 38 ]. Several key amino acid residues have been identified for substrate binding of CYP4Z1 including Arg487, Asn381, Ser383, Ser222, Ser113, and Asn381 [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…These recent advances in determining the CYP4Z1 enzyme’s substrate recognition have led to the development of selective inhibitors for CYP4Z1. The first inhibitor identified was 1-benzylimidazole, which showed efficient blocking ability for production of 14, 15-EET in CYP4Z1 positive tumour cells relative to a poor inhibitory profile against other CYPs [ 38 ]. Interestingly, a new highly potent inhibitor (Compound 9) for CYP4Z1 was developed using systematic virtual screening.…”

Section: Discussionmentioning

confidence: 99%

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Cytochrome 4Z1 Expression Is Correlated with Poor Prognosis in Patients with Cervical Cancer

et al. 2021

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Background: cervical cancer is one of the most common malignancies in women worldwide and its management remains challenging and complex. As Cytochrome4Z1 (CYP4Z1) is overexpressed in many tumours, its expression in cervical cancer is unknown. Therefore, the present study aimed to evaluate CYP4Z1 expression in cervical cancers. Methods: CYP4Z1 expression was immunohistochemically assessed in 100 cases of cervical cancers along with ten normal cervix tissues, and the enzyme’s relationship to several clinicopathological features and survival was explored. Results: CYP4Z1 was strongly expressed in 55% of cervical cancer patients. Normal cervix samples were negative for CYP4Z1 expression. Importantly, this expression was significantly found in patients with the late stage of the disease, lymph node metastasis, and high tumour invasion (p < 0.05). Interestingly, CYP4Z1 expression was significantly correlated with shorter survival times of cervical cancer patients. Univariate analysis showed that CYP4Z1 expression, tumour stage, lymph node metastasis, and tumour invasion were significantly correlated with patient survival (p < 0.05). The multivariate analysis revealed that only CYP4Z1 expression and tumour stage were significantly correlated with patient survival (p < 0.05). Conclusions: CYP4Z1 expression is associated with cervical cancer patients’ survival and may serve as an independent predictor of poor prognosis in cervical cancer patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cytochrome 4Z1 Expression Is Correlated with Poor Prognosis in Patients with Cervical Cancer

et al. 2021

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“…This inhibitor efficiently blocks the production of 14.15-EET in CYP4Z1-positive breast carcinoma cells, in contrast to weak inhibitory profiles against other CYPs. 30 These recent advances are useful for the molecular probing of the functional activities of CYP4Z1 and its involvement in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome 4Z1 Expression is Associated with Unfavorable Survival in Triple-Negative Breast Cancers

Al-saraireh¹,

Alshammari²,

Youssef³

et al. 2021

BCTT

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Triple-negative breast cancer (TNBC) is characterized by high mortality rate, and its clinical management is difficult and complex. Therefore, there is a need for extensive efforts aimed at accelerating the discovery of novel therapies for TNBC. CYP4Z1 has been implicated in the development of breast cancer. The current study aimed at characterizing the expression of CYP4Z1 on TNBC. Materials and Methods: Using immunohistochemistry, CYP4Z1 expression was evaluated on 122 TNBC samples, four samples of breast cancers expressing ER, PR, and HER-2, and four samples of normal breast tissues. The association between the enzyme and various histopathological features and survival of patients were determined. Results: CYP4Z1 was strongly expressed in 83.3% of various histopathological subtypes of TNBC, when compared to negative expression in normal breast tissues. Interestingly, there were marked variations in CYP4Z1 expression with respect to histopathology subtype, histological grade, histological stage and tumor diameter. There was a high incidence of CYP4Z1 expression in patients with advanced grades, late stages and larger tumor sizes. Importantly, CYP4Z1 expression was correlated with the survival of TNBC patients, but it was an independent determinant of the poor prognosis of TNBC (p< 0.05). Conclusion: CYP4ZI may be a potential biomarker or target for evolving new CYP4Z1targeted treatments.

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“…Moreover, since HET0016 not only targets CYP4Z1, it is necessary to develop other small molecule compounds with a stronger specificity for CYP4Z1. It is encouraging that the recent studies have screened out some other compounds with a stronger specificity for CYP4Z1, 21,42,43 like miconazole, econazole, aminobenzotriazole, tolazoline, 1‐benzylimidazole, and its derivatives. However, the roles of these above novel inhibitors of CYP4Z1 have not been revealed in breast cancer progression, which should be evaluated in the future.…”

Section: Discussionmentioning

confidence: 99%

HET0016 attenuates the stemness of breast cancer cells through targeting CYP4Z1

Liu

Qin

Zhou

et al. 2021

Molecular Carcinogenesis

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Ours and other previous studies have shown that CYP4Z1 is specifically and highly expressed in breast cancer, and acts as a promoter for the stemness of breast cancer cells. Here, we explored whether targeting CYP4Z1 could attenuate the stemness of breast cancer cells using HET0016, which has been confirmed to be an inhibitor of CYP4Z1 by us and others. Using the transcriptome‐sequencing analysis, we found that HET0016 suppressed the expression of cancer stem cell (CSC) markers and stem cell functions. Additionally, HET0016 indeed reduced the stemness of breast cancer cells, as evident by the decrease of stemness marker expression, CD44+/CD24− subpopulation with stemness, mammary‐spheroid formation, and tumor‐initiating ability. Moreover, HET0016 suppressed the metastatic capability through in vitro and in vivo experiments. Furthermore, we confirmed that HET0016 suppressed CYP4Z1 activity, and HET0016‐induced inhibition on the stemness and metastasis of breast cancer cells was rescued by CYP4Z1 overexpression. Thus, our results demonstrate that HET0016 can attenuate the stemness of breast cancer cells through targeting CYP4Z1.

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Design and Characterization of the First Selective and Potent Mechanism-Based Inhibitor of Cytochrome P450 4Z1

Cited by 17 publications

References 53 publications

Cytochrome 4Z1 Expression Is Correlated with Poor Prognosis in Patients with Cervical Cancer

Cytochrome 4Z1 Expression Is Correlated with Poor Prognosis in Patients with Cervical Cancer

Cytochrome 4Z1 Expression is Associated with Unfavorable Survival in Triple-Negative Breast Cancers

HET0016 attenuates the stemness of breast cancer cells through targeting CYP4Z1

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