Pyridine indole hybrids as novel potent CYP17A1 inhibitors
Prostate cancer (PCa) is one of the most prevalent malignancies affecting men worldwide, and androgen deprivation therapy (ADT) is a primary treatment approach. CYP17A1 inhibitors like abiraterone target the steroidogenic pathway to reduce androgen levels, but their clinical efficacy is limited by d...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2025.2463014 |
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| _version_ | 1849718703931785216 |
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| author | Tomasz M. Wróbel Angelika Grudzińska Jibira Yakubu Therina du Toit Katyayani Sharma Jeremiah C. Harrington Fredrik Björkling Flemming Steen Jørgensen Amit V. Pandey |
| author_facet | Tomasz M. Wróbel Angelika Grudzińska Jibira Yakubu Therina du Toit Katyayani Sharma Jeremiah C. Harrington Fredrik Björkling Flemming Steen Jørgensen Amit V. Pandey |
| author_sort | Tomasz M. Wróbel |
| collection | DOAJ |
| description | Prostate cancer (PCa) is one of the most prevalent malignancies affecting men worldwide, and androgen deprivation therapy (ADT) is a primary treatment approach. CYP17A1 inhibitors like abiraterone target the steroidogenic pathway to reduce androgen levels, but their clinical efficacy is limited by drug resistance and adverse effects. This study reports the synthesis and evaluation of novel CYP17A1 inhibitors derived from a previously identified hit compound. Several analogs were synthesised, including an unexpected di-cyano derivative, which demonstrated increased potency against CYP17A1 compared to abiraterone. Biological assays revealed that these compounds significantly inhibited CYP17A1 enzymatic activity and altered steroid biosynthesis. Among the newly synthesised inhibitors, compound 11 showed the highest potency (IC50 = 4 nM) and the related compound 14 presented a template for further development. A combined docking and molecular dynamics approach was used to identify the possible target binding modes of the compounds. |
| format | Article |
| id | doaj-art-2b0f63253cc24dfc970b0890757145a1 |
| institution | DOAJ |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-2b0f63253cc24dfc970b0890757145a12025-08-20T03:12:19ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742025-12-0140110.1080/14756366.2025.2463014Pyridine indole hybrids as novel potent CYP17A1 inhibitorsTomasz M. Wróbel0Angelika Grudzińska1Jibira Yakubu2Therina du Toit3Katyayani Sharma4Jeremiah C. Harrington5Fredrik Björkling6Flemming Steen Jørgensen7Amit V. Pandey8Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University of Lublin, Lublin, PolandDepartment of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University of Lublin, Lublin, PolandPediatric Endocrinology, Department of Pediatrics, University Children’s Hospital, University of Bern, Bern, SwitzerlandDepartment of Nephrology and Hypertension, University Hospital Bern, Inselspital, University of Bern, Bern, SwitzerlandPediatric Endocrinology, Department of Pediatrics, University Children’s Hospital, University of Bern, Bern, SwitzerlandDepartment of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, DenmarkDepartment of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, DenmarkDepartment of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, DenmarkPediatric Endocrinology, Department of Pediatrics, University Children’s Hospital, University of Bern, Bern, SwitzerlandProstate cancer (PCa) is one of the most prevalent malignancies affecting men worldwide, and androgen deprivation therapy (ADT) is a primary treatment approach. CYP17A1 inhibitors like abiraterone target the steroidogenic pathway to reduce androgen levels, but their clinical efficacy is limited by drug resistance and adverse effects. This study reports the synthesis and evaluation of novel CYP17A1 inhibitors derived from a previously identified hit compound. Several analogs were synthesised, including an unexpected di-cyano derivative, which demonstrated increased potency against CYP17A1 compared to abiraterone. Biological assays revealed that these compounds significantly inhibited CYP17A1 enzymatic activity and altered steroid biosynthesis. Among the newly synthesised inhibitors, compound 11 showed the highest potency (IC50 = 4 nM) and the related compound 14 presented a template for further development. A combined docking and molecular dynamics approach was used to identify the possible target binding modes of the compounds.https://www.tandfonline.com/doi/10.1080/14756366.2025.2463014CYP17A1enzyme inhibitionprostate cancerinhibitors |
| spellingShingle | Tomasz M. Wróbel Angelika Grudzińska Jibira Yakubu Therina du Toit Katyayani Sharma Jeremiah C. Harrington Fredrik Björkling Flemming Steen Jørgensen Amit V. Pandey Pyridine indole hybrids as novel potent CYP17A1 inhibitors Journal of Enzyme Inhibition and Medicinal Chemistry CYP17A1 enzyme inhibition prostate cancer inhibitors |
| title | Pyridine indole hybrids as novel potent CYP17A1 inhibitors |
| title_full | Pyridine indole hybrids as novel potent CYP17A1 inhibitors |
| title_fullStr | Pyridine indole hybrids as novel potent CYP17A1 inhibitors |
| title_full_unstemmed | Pyridine indole hybrids as novel potent CYP17A1 inhibitors |
| title_short | Pyridine indole hybrids as novel potent CYP17A1 inhibitors |
| title_sort | pyridine indole hybrids as novel potent cyp17a1 inhibitors |
| topic | CYP17A1 enzyme inhibition prostate cancer inhibitors |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2025.2463014 |
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