1. AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications
- Author
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Pippione, Agnese C., Vigato, Chiara, Tucciarello, Cristina, Hussain, Samrina, Salladini, Edoardo, Truong, Ha H., Henriksen, Niel M., Vanzetti, Gaia, Giordano, Giorgia, Zonari, Daniele, Mirza, Osman Asghar, Frydenvang, Karla, Pignochino, Ymera, Oliaro-Bosso, Simonetta, Boschi, Donatella, Lolli, Marco L., Pippione, Agnese C., Vigato, Chiara, Tucciarello, Cristina, Hussain, Samrina, Salladini, Edoardo, Truong, Ha H., Henriksen, Niel M., Vanzetti, Gaia, Giordano, Giorgia, Zonari, Daniele, Mirza, Osman Asghar, Frydenvang, Karla, Pignochino, Ymera, Oliaro-Bosso, Simonetta, Boschi, Donatella, and Lolli, Marco L.
- 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.
- Published
- 2024