AKR1C3 is an upregulated enzyme in prostate and other cancers; in addition to regulating hormone synthesis, this enzyme is thought to play a role in the aggressiveness of tumors and in the defense against drugs. We here used an unbiased method to discover new potent AKR1C3 inhibitors: through an AI-based virtual drug screen, compound 4 was identified as a potent and selective enzymatic inhibitor able to translate this activity into a pronounced antiproliferative effect in the 22RV1 prostate cancer cell model. As other known AKR1C3 inhibitors, compound 4 determined a significantly increased activity of abiraterone, a drug approved for advanced prostate cancer. Compound 4 also showed a synergic effect with doxorubicin in osteosarcoma cell lines; specifically, the effect is correlated with AKR1C3 expression. In this research work, therefore, the use of AI allowed the identification of a new structure as an AKR1C3 inhibitor and its potential to enhance the effect of chemotherapeutics.

AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications

Pippione, Agnese C.
First
;
Vigato, Chiara;Tucciarello, Cristina;Salladini, Edoardo;Vanzetti, Gaia;Giordano, Giorgia;Zonari, Daniele;Mirza, Osman Asghar;Pignochino, Ymera;Oliaro-Bosso, Simonetta
;
Boschi, Donatella
;
Lolli, Marco L.
Last
2024-01-01

Abstract

AKR1C3 is an upregulated enzyme in prostate and other cancers; in addition to regulating hormone synthesis, this enzyme is thought to play a role in the aggressiveness of tumors and in the defense against drugs. We here used an unbiased method to discover new potent AKR1C3 inhibitors: through an AI-based virtual drug screen, compound 4 was identified as a potent and selective enzymatic inhibitor able to translate this activity into a pronounced antiproliferative effect in the 22RV1 prostate cancer cell model. As other known AKR1C3 inhibitors, compound 4 determined a significantly increased activity of abiraterone, a drug approved for advanced prostate cancer. Compound 4 also showed a synergic effect with doxorubicin in osteosarcoma cell lines; specifically, the effect is correlated with AKR1C3 expression. In this research work, therefore, the use of AI allowed the identification of a new structure as an AKR1C3 inhibitor and its potential to enhance the effect of chemotherapeutics.
2024
15
8
1269
1278
https://pubs.acs.org/doi/epdf/10.1021/acsmedchemlett.4c00150
AKR1C3 inhibitors, AI drug design, Prostate Cancer, Osteosarcoma, doxorubicin
Pippione, Agnese C.; Vigato, Chiara; Tucciarello, Cristina; Hussain, Samrina; Salladini, Edoardo; Truong, Ha H.; Henriksen, Niel M.; Vanzetti, Gaia; G...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1998350
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