Potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic acid

Autor: Davide Bonanni, Marco Lucio Lolli, Weixiao Yuan Wahlgren, Rosmarie Friemann, Renzo Bagnati, Daniele Zonari, Agnese Chiara Pippione, Simonetta Oliaro-Bosso, Donatella Boschi, Parveen Goyal, Salvatore Adinolfi, Claudio Festuccia, Klaus Pors, Elisabetta Marini, Irene Maria Carnovale, Marcella Sini
Rok vydání: 2018
Předmět:
17β-HSD5
0301 basic medicine
Aldo-keto reductase 1C3
Triazole
Antineoplastic Agents
Reductase
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cell Line
Tumor
Drug Discovery
medicine
Humans
Moiety
Enzalutamide
Testosterone
CRPC
Enzyme Inhibitors
Cell Proliferation
Prostate cancer (PCa)
X-ray crystallography
Bioisosterism
Pharmacology
Benzoxazoles
Aldo-keto reductase
Scaffold hopping
Dose-Response Relationship
Drug
Molecular Structure
Inhibitors
Chemistry
Cell growth
Organic Chemistry
Aldo-Keto Reductase Family 1 Member C3
General Medicine
Prostate-Specific Antigen
AKR1C3
Flufenamic Acid
030104 developmental biology
Flufenamic acid
Biochemistry
030220 oncology & carcinogenesis
Aldo-keto reductase 1C3
AKR1C3
17β-HSD5
Prostate cancer (PCa)
CRPC
Bioisosterism
Scaffold hopping
Inhibitors
X-ray crystallography
Drug Screening Assays
Antitumor
Pharmacophore
medicine.drug
Zdroj: European Journal of Medicinal Chemistry. 150:930-945
ISSN: 0223-5234
Popis: The aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. Recently, we employed a scaffold hopping approach to design a new class of potent and selective AKR1C3 inhibitors based on a N-substituted hydroxylated triazole pharmacophore. Following a similar strategy, we designed a new series focused around an acidic hydroxybenzoisoxazole moiety, which was rationalised to mimic the benzoic acid role in the flufenamic scaffold. Through iterative rounds of drug design, synthesis and biological evaluation, several compounds were discovered to target AKR1C3 in a selective manner. The most promising compound of series (6) was found to be highly selective (up to 450-fold) for AKR1C3 over the 1C2 isoform with minimal COX1 and COX2 off-target effects. Other inhibitors were obtained modulating the best example of hydroxylated triazoles we previously presented. In cell-based assays, the most promising compounds of both series reduced the cell proliferation, prostate specific antigen (PSA) and testosterone production in AKR1C3-expressing 22RV1 prostate cancer cells and showed synergistic effect when assayed in combination with abiraterone and enzalutamide. Structure determination of AKR1C3 co-crystallized with one representative compound from each of the two series clearly identified both compounds in the androstenedione binding site, hence supporting the biochemical data.
Databáze: OpenAIRE
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