Structure-guided optimization of 3-hydroxybenzoisoxazole derivatives as inhibitors of Aldo-keto reductase 1C3 (AKR1C3) to target prostate cancer
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Structure-guided optimization of 3-hydroxybenzoisoxazole derivatives as inhibitors of Aldo-keto reductase 1C3 (AKR1C3) to target prostate cancer. / Pippione, Agnese Chiara; Kovachka, Sandra; Vigato, Chiara; Bertarini, Laura; Mannella, Iole; Sainas, Stefano; Rolando, Barbara; Denasio, Enrica; Piercy-Mycock, Helen; Romalho, Linda; Salladini, Edoardo; Adinolfi, Salvatore; Zonari, Daniele; Peraldo-Neia, Caterina; Chiorino, Giovanna; Passoni, Alice; Mirza, Osman Asghar; Frydenvang, Karla; Pors, Klaus; Lolli, Marco Lucio; Spyrakis, Francesca; Oliaro-Bosso, Simonetta; Boschi, Donatella.
In: European Journal of Medicinal Chemistry, Vol. 268, 116193, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Structure-guided optimization of 3-hydroxybenzoisoxazole derivatives as inhibitors of Aldo-keto reductase 1C3 (AKR1C3) to target prostate cancer
AU - Pippione, Agnese Chiara
AU - Kovachka, Sandra
AU - Vigato, Chiara
AU - Bertarini, Laura
AU - Mannella, Iole
AU - Sainas, Stefano
AU - Rolando, Barbara
AU - Denasio, Enrica
AU - Piercy-Mycock, Helen
AU - Romalho, Linda
AU - Salladini, Edoardo
AU - Adinolfi, Salvatore
AU - Zonari, Daniele
AU - Peraldo-Neia, Caterina
AU - Chiorino, Giovanna
AU - Passoni, Alice
AU - Mirza, Osman Asghar
AU - Frydenvang, Karla
AU - Pors, Klaus
AU - Lolli, Marco Lucio
AU - Spyrakis, Francesca
AU - Oliaro-Bosso, Simonetta
AU - Boschi, Donatella
N1 - Publisher Copyright: © 2024 The Authors
PY - 2024
Y1 - 2024
N2 - 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 IC50 values in series (2.3, 2.0 and 2.4 μM 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.
AB - 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 IC50 values in series (2.3, 2.0 and 2.4 μM 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.
KW - AKR1C3 inhibitors
KW - Benzoisoxazoles
KW - Prostate cancer
KW - X-ray crystallography
U2 - 10.1016/j.ejmech.2024.116193
DO - 10.1016/j.ejmech.2024.116193
M3 - Journal article
C2 - 38364714
VL - 268
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
M1 - 116193
ER -
ID: 384573411