Structure-guided optimization of 3-hydroxybenzoisoxazole derivatives as inhibitors of Aldo-keto reductase 1C3 (AKR1C3) to target prostate cancer

被引：6

作者：

Pippione, Agnese Chiara ^{[1
]}

Kovachka, Sandra ^{[1
,2
]}

Vigato, Chiara ^{[1
]}

Bertarini, Laura ^{[1
,3
]}

Mannella, Iole ^{[1
]}

Sainas, Stefano ^{[1
]}

Rolando, Barbara ^{[1
]}

Denasio, Enrica ^{[4
]}

Piercy-Mycock, Helen ^{[4
]}

Romalho, Linda ^{[5
]}

Salladini, Edoardo ^{[1
]}

Adinolfi, Salvatore ^{[1
]}

Zonari, Daniele ^{[1
]}

Peraldo-Neia, Caterina ^{[6
]}

Chiorino, Giovanna ^{[6
]}

Passoni, Alice ^{[7
]}

Mirza, Osman Asghar ^{[5
]}

Frydenvang, Karla ^{[5
]}

Pors, Klaus ^{[4
]}

Lolli, Marco Lucio ^{[1
]}

Spyrakis, Francesca ^{[1
]}

Oliaro-Bosso, Simonetta ^{[1
]}

Boschi, Donatella ^{[1
]}

机构：

[1] Univ Turin, Dept Sci & Drug Technol, via Pietro Giuria 9, I-10125 Turin, Italy

[2] Herbert Wertheim UF Scripps Inst Biomed Innovat &, Herbert Wertheim UF Scripps Inst Biomed Innovat &, Dept Neurosci, Jupiter, FL USA

[3] Univ Modena & Reggio Emilia, Dept Life Sci, via Campi 103, I-41125 Modena, Italy

[4] Univ Bradford, Inst Canc Therapeut, Fac Life Sci, Bradford BD7, England

[5] Univ Copenhagen, Dept Drug Design & Pharmacol, Jagtvej 162, DK-2100 Copenhagen, Denmark

[6] Fdn Edo & Elvo Tempia, Lab Canc Genom, Via Malta 3, I-13900 Biella, Italy

[7] Ist Ric Farmacolog Mario Negri IRCCS, Dept Environm Hlth Sci, Via Mario Negri 2, I-20156 Milan, Italy

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 268卷

关键词：

AKR1C3; inhibitors; Prostate cancer; Benzoisoxazoles; X-ray crystallography; PRODRUG PR-104A; 17-BETA-HYDROXYSTEROID-DEHYDROGENASE; ACTIVATION; RESISTANCE; PROTEIN; INSIGHTS; MARKER; POTENT; CELLS; MODEL;

D O I：

10.1016/j.ejmech.2024.116193

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 degrees 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 IC50 values in series (2.3, 2.0 and 2.4 mu M respectively) and showed no toxicity towards human MRC-5 cells. Co-treatment with scalar dilutions of either compound 6 or 6e and the clinically used drug abiraterone led to a significant reduction in cell proliferation, and thus confirmed that treatment with both CYP171A1-and AKR1C3-targeting compounds possess the potential to intervene in key steps in the steroidogenic pathway. Taken together, the novel compounds display desirable biochemical potency and cellular target inhibition as well as good in-vitro ADME properties, which highlight their potential for further preclinical studies.

引用

页数：20