دورية أكاديمية
Structure-guided optimization of 3-hydroxybenzoisoxazole derivatives as inhibitors of Aldo-keto reductase 1C3 (AKR1C3) to target prostate cancer.
| العنوان: | Structure-guided optimization of 3-hydroxybenzoisoxazole derivatives as inhibitors of Aldo-keto reductase 1C3 (AKR1C3) to target prostate cancer. |
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| المؤلفون: | Pippione AC; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy., Kovachka S; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy; The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA., Vigato C; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy., Bertarini L; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy; Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125, Modena, Italy., Mannella I; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy., Sainas S; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy., Rolando B; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy., Denasio E; Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, West Yorkshire, BD7 1DP, UK., Piercy-Mycock H; Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, West Yorkshire, BD7 1DP, UK., Romalho L; Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, DK-2100, Copenhagen, Denmark., Salladini E; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy., Adinolfi S; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy., Zonari D; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy., Peraldo-Neia C; Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, via Malta 3, 13900, Biella, Italy., Chiorino G; Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, via Malta 3, 13900, Biella, Italy., Passoni A; Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy., Mirza OA; Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, DK-2100, Copenhagen, Denmark., Frydenvang K; Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, DK-2100, Copenhagen, Denmark., Pors K; Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, West Yorkshire, BD7 1DP, UK., Lolli ML; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy., Spyrakis F; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy., Oliaro-Bosso S; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy. Electronic address: simona.oliaro@unito.it., Boschi D; Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125, Turin, Italy. Electronic address: donatella.boschi@unito.it. |
| المصدر: | European journal of medicinal chemistry [Eur J Med Chem] 2024 Mar 15; Vol. 268, pp. 116193. Date of Electronic Publication: 2024 Feb 07. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Paris : Editions Scientifiques Elsevier Original Publication: Paris, S.E.C.T. [etc.] |
| مواضيع طبية MeSH: | Prostatic Neoplasms*/drug therapy, Male ; Humans ; Aldo-Keto Reductase Family 1 Member C3 ; 3-Hydroxysteroid Dehydrogenases/metabolism ; Hydroxyprostaglandin Dehydrogenases/metabolism ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/chemistry |
| مستخلص: | AKR1C3 is an enzyme that is overexpressed in several types of radiotherapy- and chemotherapy-resistant cancers. Despite AKR1C3 is a validated target for drug development, no inhibitor has been approved for clinical use. In this manuscript, we describe our study of a new series of potent AKR1C3-targeting 3-hydroxybenzoisoxazole based inhibitors that display high selectivity over the AKR1C2 isoform and low micromolar activity in inhibiting 22Rv1 prostate cancer cell proliferation. In silico studies suggested proper substituents to increase compound potency and provided with a mechanistic explanation that could clarify their different activity, later confirmed by X-ray crystallography. Both the in-silico studies and the crystallographic data highlight the importance of 90° rotation around the single bond of the biphenyl group, in ensuring that the inhibitor can adopt the optimal binding mode within the active pocket. The p-biphenyls that bear the meta-methoxy, and the ortho- and meta-trifluoromethyl substituents (in compounds 6a, 6e and 6f respectively) proved to be the best contributors to cellular potency as they provided the best IC Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.) |
| فهرسة مساهمة: | Keywords: AKR1C3 inhibitors; Benzoisoxazoles; Prostate cancer; X-ray crystallography |
| المشرفين على المادة: | EC 1.1.1.357 (Aldo-Keto Reductase Family 1 Member C3) EC 1.1.- (3-Hydroxysteroid Dehydrogenases) EC 1.1.1.- (Hydroxyprostaglandin Dehydrogenases) 0 (Enzyme Inhibitors) EC 1.1.1.357 (AKR1C3 protein, human) |
| تواريخ الأحداث: | Date Created: 20240216 Date Completed: 20240318 Latest Revision: 20240318 |
| رمز التحديث: | 20240318 |
| DOI: | 10.1016/j.ejmech.2024.116193 |
| PMID: | 38364714 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1768-3254 |
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| DOI: | 10.1016/j.ejmech.2024.116193 |