Non-steroidal CYP17A1 Inhibitors: Discovery and Assessment

Wróbel, Tomasz M.; Jørgensen, Flemming Steen; Pandey, Amit V.; Grudzińska, Angelika; Sharma, Katyayani; Jibira, Yakubu; Björkling, Fredrik

doi:10.1021/acs.jmedchem.3c00442

Cited by 18 publications

(13 citation statements)

References 196 publications

(405 reference statements)

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“…CYP17A1 targeted drugs have been developed over the years for the treatment of PCa as well as Castration Resistance Prostate Cancer (CRPC) [68]. Therefore, CYP17A1 has emerged as an attractive target for the design of inhibitors to use as drugs against prostate cancer [69]. From a non-selective Cytochrome P450 inhibitor, Ketoconazole, first-generation CYP17A1 targeted drugs such as Abiraterone and Orteronel (TAK700) to the most recent compounds with better selectivity towards 17,20 Lyase activity like Galeterone (TOK-001) and VT464, there is a continuous search for more efficient and potent inhibitors to overcome the challenges due to their adverse side-effects [70] [71] [72] [73] [74] [75-78].…”

Section: Discussionmentioning

confidence: 99%

Essential oil terpenes may inhibit steroidogenic cytochrome P450 activities

Sharma,

Lanzilotto,

Yakubu

et al. 2023

Preprint

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Endocrine-disrupting chemicals (EDCs) may impact the development of Prostate Cancer (PCa) by altering the steroid metabolism. Although their exact mechanism of action in controlling tumor growth is not known, EDCs may inhibit steroidogenic enzymes such as Cytochrome P450 c17 (CYP17A1) or aromatase (CYP19A1) involved in the production of Androgens or Estrogens. High levels of circulating androgens are linked to PCa in men and Polycystic Ovary Syndrome (PCOS) in women. Essential Oils or their metabolites (EOs) like lavender oil and tea tree oil have been reported to act as potential EDCs and contribute towards sex steroid imbalance in case of prepubertal gynecomastia in boys and premature thelarche in girls due to the regular exposure to lavender-based fragrances among Hispanic population. We screened a range of EO components to determine their effects on CYP17A1 and CYP19A1 Computational docking was performed to predict the binding of EOs with CYP17A1 and CYP19A1 and functional assays were done using the radiolabeled substrates or Liquid Chromatography high-resolution Mass Spectrometry and cell viability assays were carried out in LNCaP cells. Many of the tested compounds bind close to the active site of CYP17A1, and (+)-Cedrol had the best binding with CYP17A1 and CYP19A1. Eucalyptol, Dihydro-β-Ionone & (-)-α-pinene showed 20% to 40% inhibition of dehydroepiandrosterone production; and some compounds also effected CYP19A1. Extensive use of these EOs in various beauty and hygiene products is common, but only a limited knowledge about their potential detrimental side effects exists. Our results suggest that prolonged exposure to some of these essential oils may result in steroid imbalances. On the other hand, due to their effect on lowering androgen output, ability to bind at the active site of steroidogenic cytochrome P450s, these compounds may provide design ideas for the novel compounds against hyperandrogenic disorders such as PCa and PCOS.

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Section: Discussionmentioning

confidence: 99%

Essential oil terpenes may inhibit steroidogenic cytochrome P450 activities

Sharma,

Lanzilotto,

Yakubu

et al. 2023

Preprint

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“…Abiraterone acetate is an irreversible, selective inhibitor of cytochrome p450 17A1 (CYP17), which blocks the production of androgen in men with mCRPC [ 133 – 135 ]. Abiraterone, has been shown to provide a survival benefit and therefore approved for the treatment of mCRPC [ 136 – 138 ] by targeting androgen pathway (Fig.…”

Section: Novel Hormone Therapiesmentioning

confidence: 99%

Recent advances and future perspectives in the therapeutics of prostate cancer

Varaprasad,

Gupta,

Prasad

et al. 2023

Exp Hematol Oncol

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Prostate cancer (PC) is one of the most common cancers in males and the fifth leading reason of death. Age, ethnicity, family history, and genetic defects are major factors that determine the aggressiveness and lethality of PC. The African population is at the highest risk of developing high-grade PC. It can be challenging to distinguish between low-risk and high-risk patients due to the slow progression of PC. Prostate-specific antigen (PSA) is a revolutionary discovery for the identification of PC. However, it has led to an increase in over diagnosis and over treatment of PC in the past few decades. Even if modifications are made to the standard PSA testing, the specificity has not been found to be significant. Our understanding of PC genetics and proteomics has improved due to advances in different fields. New serum, urine, and tissue biomarkers, such as PC antigen 3 (PCA3), have led to various new diagnostic tests, such as the prostate health index, 4K score, and PCA3. These tests significantly reduce the number of unnecessary and repeat biopsies performed. Chemotherapy, radiotherapy, and prostatectomy are standard treatment options. However, newer novel hormone therapy drugs with a better response have been identified. Androgen deprivation and hormonal therapy are evolving as new and better options for managing hormone-sensitive and castration-resistant PC. This review aimed to highlight and discuss epidemiology, various risk factors, and developments in PC diagnosis and treatment regimens.

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“…The inhibition of CYP17A1 results in decreased androgen production and has emerged as a promising strategy for the treatment of PCa ( Figure 2 ) [ 4 ]. CYP17A1 inhibitors can be classified into two categories: steroidal represented by abiraterone, and nonsteroidal [ 5 ]. Abiraterone is the only CYP17A1 inhibitor that has been approved as a drug for clinical use in the treatment of CRPC.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Potential of Sulfur Moieties in Compounds Inhibiting Steroidogenesis

Wróbel,

Sharma,

Mannella

et al. 2023

Biomolecules

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This study reports on the synthesis and evaluation of novel compounds replacing the nitrogen-containing heterocyclic ring on the chemical backbone structure of cytochrome P450 17α-hydroxylase/12,20-lyase (CYP17A1) inhibitors with a phenyl bearing a sulfur-based substituent. Initial screening revealed compounds with marked inhibition of CYP17A1 activity. The selectivity of compounds was thereafter determined against cytochrome P450 21-hydroxylase, cytochrome P450 3A4, and cytochrome P450 oxidoreductase. Additionally, the compounds showed weak inhibitory activity against aldo-keto reductase 1C3 (AKR1C3). The compounds’ impact on steroid hormone levels was also assessed, with some notable modulatory effects observed. This work paves the way for developing more potent dual inhibitors specifically targeting CYP17A1 and AKR1C3.

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Non-steroidal CYP17A1 Inhibitors: Discovery and Assessment

Cited by 18 publications

References 196 publications

Essential oil terpenes may inhibit steroidogenic cytochrome P450 activities

Essential oil terpenes may inhibit steroidogenic cytochrome P450 activities

Recent advances and future perspectives in the therapeutics of prostate cancer

Exploring the Potential of Sulfur Moieties in Compounds Inhibiting Steroidogenesis

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