Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents

Wróbel, Tomasz M.; Rogova, Oksana; Sharma, Katyayani; Velazquez, Maria Natalia Rojas; Pandey, Amit V.; Jørgensen, Flemming Steen; Arendrup, Frederic S; Andersen, Kasper Langebjerg; Björkling, Fredrik

doi:10.3390/biom12020165

Cited by 13 publications

(9 citation statements)

References 42 publications

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“…There are a few previous studies focusing on the structure–activity relationship of CYP17A1 inhibitors [ 17 , 18 , 19 ]. Previous studies focused on singular scaffolds or worked through 3D pharmacophore models.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Chemical Space of CYP17A1 Inhibitors Using Cheminformatics and Machine Learning

Huang

et al. 2023

Molecules

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Cytochrome P450 17A1 (CYP17A1) is one of the key enzymes in steroidogenesis that produces dehydroepiandrosterone (DHEA) from cholesterol. Abnormal DHEA production may lead to the progression of severe diseases, such as prostatic and breast cancers. Thus, CYP17A1 is a druggable target for anti-cancer molecule development. In this study, cheminformatic analyses and quantitative structure–activity relationship (QSAR) modeling were applied on a set of 962 CYP17A1 inhibitors (i.e., consisting of 279 steroidal and 683 nonsteroidal inhibitors) compiled from the ChEMBL database. For steroidal inhibitors, a QSAR classification model built using the PubChem fingerprint along with the extra trees algorithm achieved the best performance, reflected by the accuracy values of 0.933, 0.818, and 0.833 for the training, cross-validation, and test sets, respectively. For nonsteroidal inhibitors, a systematic cheminformatic analysis was applied for exploring the chemical space, Murcko scaffolds, and structure–activity relationships (SARs) for visualizing distributions, patterns, and representative scaffolds for drug discoveries. Furthermore, seven total QSAR classification models were established based on the nonsteroidal scaffolds, and two activity cliff (AC) generators were identified. The best performing model out of these seven was model VIII, which is built upon the PubChem fingerprint along with the random forest algorithm. It achieved a robust accuracy across the training set, the cross-validation set, and the test set, i.e., 0.96, 0.92, and 0.913, respectively. It is anticipated that the results presented herein would be instrumental for further CYP17A1 inhibitor drug discovery efforts.

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Section: Discussionmentioning

confidence: 99%

Exploring the Chemical Space of CYP17A1 Inhibitors Using Cheminformatics and Machine Learning

Huang

et al. 2023

Molecules

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“…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]. For instance, in addition to CYP17A1, Abiraterone also targets cytochrome P450 21-hydroxylase (CYP21A2) activity, which is essential for aldosterone and cortisol production [79, 80].…”

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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“…When searching for potential treatment options in autism, pharmaceuticals directly addressing CYP17A1 activity—especially 17/20 Lyase activity—should be considered as therapeutical targets. These pharmaceuticals, for example, abiraterone, are mainly known for the treatment of prostate cancer to reduce androgen concentrations [ 40 , 41 , 42 ]. Furthermore, Metformin might be an opportunity which is used for the metabolic consequences seen in polycystic ovary syndrome for its androgen-lowering and insulin-sensitizing properties [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

How Is CYP17A1 Activity Altered in Autism? A Pilot Study to Identify Potential Pharmacological Targets

Gasser

Kurz²,

Dick

et al. 2022

Life

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Background: Increasing evidence exists that higher levels of androgens can be found in individuals with autism. Evidence yields to a susceptible role of Cytochrome P450 17A1 (CYP17A1) with its catalyzation of the two distinct types of substrate oxidation by a hydroxylase activity (17-alpha hydroxylase) and C17/20 lyase activity. However, to what extent steps are altered in affected children with autism versus healthy controls remains to be elucidated. Methods: Urine samples from 48 boys with autism (BMI 19.1 ± 0.6 kg/m2, age 14.2 ± 0.5 years) and a matched cohort of 48 healthy boys (BMI 18.6 ± 0.3 kg/m2, 14.3 ± 0.5 years) as well as 16 girls with autism (BMI 17.5 ± 0.7 kg/m2, age 13.8 ± 1.0 years) and a matched cohort of 16 healthy girls (BMI 17.2 ± 0.8 kg/m2, age 13.2 ± 0.8 years) were analyzed for steroid hormone metabolites by gas chromatography-mass spectrometry. Results: The activity of 17-alpha Hydroxylase increased by almost 50%, whereas activity of 17/20 Lyase activity increased by around 150% in affected children with autism. Furthermore, the concentration of Cortisol was higher as compared to the average increase of the three metabolites TH-Corticosterone, 5α-TH-Corticosterone and TH-11β-DH-Corticosterone, indicating, in addition, a stimulation by the CRH-ACTH system despite a higher enzymatic activity. Discussion: As it was shown that oxidative stress increases the 17/20-lyase activity via p38α, a link between higher steroid hormone levels and oxidative stress can be established. However, as glucocorticoid as well as androgen metabolites showed higher values in subjects affected with autism as compared to healthy controls, the data indicate, despite higher CYP17A1 activity, the presence of increased substrate availability in line with the Cholesterol theory of autism.

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Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents

Cited by 13 publications

References 42 publications

Exploring the Chemical Space of CYP17A1 Inhibitors Using Cheminformatics and Machine Learning

Exploring the Chemical Space of CYP17A1 Inhibitors Using Cheminformatics and Machine Learning

Essential oil terpenes may inhibit steroidogenic cytochrome P450 activities

How Is CYP17A1 Activity Altered in Autism? A Pilot Study to Identify Potential Pharmacological Targets

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