AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications
Publikation: Bidrag til tidsskrift › Letter › Forskning › fagfællebedømt
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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | ACS Medicinal Chemistry Letters |
| ISSN | 1948-5875 |
| DOI | |
| Status | Accepteret/In press - 2024 |
Bibliografisk note
Funding Information:
This work was supported by the University of Turin (Ricerca Locale grants BOSD_RILO_22_01, LOLM_RILO_21_01, PIPA_RILO_21_01, PIPA_RILO_22_01, OLIS_RILO_22_02, Grant for Internationalization PIPA_GFI_22_01_F), Fondazione Cassa di Risparmio di Torino (Grant BOSD_CRT_17_2 and OLIS_CRT_22_01), Ministero della Salute-Ricerca Finalizzata-Giovani Ricercatori GR-2016\u201302362726 to YP.
Funding Information:
We gratefully thank Prof. Flemming Steen J\u00F8rgensen (University of Copenhagen) for his help in state-of-the-art calculations for the p K -value for the tertiary amine of compound 4 . We thank Dr. Giovanna Chiorino and Dr. Caterina Peraldo-Neia (Fondazione Edo ed Elvo Tempia) and Prof. Tomasz Wrobel (Medical University of Lublin) for helpful discussion on AKR1C3 inhibitor research and support help us create an effective collaboration network. We acknowledge MAX IV Laboratory for time on Beamline Biomax under Proposal 20220195. Research conducted at MAX IV, a Swedish national user facility, is supported by the Swedish Research council under contract 2018-07152, the Swedish Governmental Agency for Innovation Systems under contract 2018-04969, and Formas under contract 2019-02496. a
Publisher Copyright:
© 2024 American Chemical Society
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