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Pyridine indole hybrids as novel potent CYP17A1 inhibitors

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Title: Pyridine indole hybrids as novel potent CYP17A1 inhibitors
Authors: Wróbel, Tomasz M, Grudzińska, Angelika, Yakubu, Jibira, Du Toit, Therina, Sharma, Katyayani, Harrington, Jeremiah C, Björkling, Fredrik, Jørgensen, Flemming Steen, Pandey, Amit Vikram
Source: J Enzyme Inhib Med Chem
Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 40, Iss 1 (2025)
Wróbel, T M, Grudzińska, A, Yakubu, J, du Toit, T, Sharma, K, Harrington, J C, Björkling, F, Jørgensen, F S & Pandey, A V 2025, ' Pyridine indole hybrids as novel potent CYP17A1 inhibitors ', Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 40, no. 1, 2463014 . https://doi.org/10.1080/14756366.2025.2463014
Publisher Information: Informa UK Limited, 2025.
Publication Year: 2025
Subject Terms: Pyridines/pharmacology, Enzyme Inhibitors/pharmacology, Indoles, Molecular Structure, Dose-Response Relationship, Drug, Pyridines, Steroid 17-alpha-Hydroxylase, RM1-950, Steroid 17-alpha-Hydroxylase/antagonists & inhibitors, prostate cancer, Dose-Response Relationship, Indoles/chemistry, Molecular Docking Simulation, Structure-Activity Relationship, CYP17A1, inhibitors, Humans, Therapeutics. Pharmacology, Drug, Enzyme Inhibitors, enzyme inhibition, Research Article
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.
Document Type: Article
Other literature type
File Description: application/pdf
Language: English
ISSN: 1475-6374
1475-6366
DOI: 10.1080/14756366.2025.2463014
DOI: 10.6084/m9.figshare.28418082
DOI: 10.6084/m9.figshare.28418082.v1
DOI: 10.48620/85471
Access URL: https://pubmed.ncbi.nlm.nih.gov/39950830
https://doaj.org/article/2b0f63253cc24dfc970b0890757145a1
https://curis.ku.dk/ws/files/428678784/Pyridine_indole_hybrids_as_novel_potent_CYP17A1_inhibitors.pdf
Rights: CC BY
URL: http://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
Accession Number: edsair.doi.dedup.....066bce15f30b352549f0284dc0e1d0bb
Database: OpenAIRE
Description
Abstract: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.
ISSN:14756374
14756366
DOI:10.1080/14756366.2025.2463014