AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications

Agnese C. Pippione; Chiara Vigato; Cristina Tucciarello; Samrina Hussain; Edoardo Salladini; Ha H. Truong; Niel M. Henriksen; Gaia Vanzetti; Giorgia Giordano; Daniele Zonari; Osman Asghar Mirza; Karla Frydenvang; Ymera Pignochino; Simonetta Oliaro-Bosso; Donatella Boschi; Marco L. Lolli

doi:10.1021/acsmedchemlett.4c00150

AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications

Agnese C. Pippione, Chiara Vigato, Cristina Tucciarello, Samrina Hussain, Edoardo Salladini, Ha H. Truong, Niel M. Henriksen, Gaia Vanzetti, Giorgia Giordano, Daniele Zonari, Osman Asghar Mirza, Karla Frydenvang, Ymera Pignochino, Simonetta Oliaro-Bosso^*, Donatella Boschi^*, Marco L. Lolli

^*Corresponding author for this work

Research output: Contribution to journal › Letter › peer-review

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.

Original language	English
Journal	ACS Medicinal Chemistry Letters
Volume	15
Issue number	8
Pages (from-to)	1269–1278
ISSN	1948-5875
DOIs	https://doi.org/10.1021/acsmedchemlett.4c00150
Publication status	Published - 2024

Bibliographical note

Publisher Copyright:
© 2024 American Chemical Society

Keywords

AI drug design
AKR1C3 inhibitors
doxorubicin.
Osteosarcoma
Prostate Cancer

Access to Document

10.1021/acsmedchemlett.4c00150

Cite this

Pippione, A. C., Vigato, C., Tucciarello, C., Hussain, S., Salladini, E., Truong, H. H., Henriksen, N. M., Vanzetti, G., Giordano, G., Zonari, D., Mirza, O. A., Frydenvang, K., Pignochino, Y., Oliaro-Bosso, S., Boschi, D., & Lolli, M. L. (2024). AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications. ACS Medicinal Chemistry Letters, 15(8), 1269–1278. https://doi.org/10.1021/acsmedchemlett.4c00150

Pippione, AC, Vigato, C, Tucciarello, C, Hussain, S , Salladini, E, Truong, HH, Henriksen, NM, Vanzetti, G, Giordano, G, Zonari, D, Mirza, OA , Frydenvang, K, Pignochino, Y, Oliaro-Bosso, S, Boschi, D & Lolli, ML 2024, 'AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications', ACS Medicinal Chemistry Letters, vol. 15, no. 8, pp. 1269–1278. https://doi.org/10.1021/acsmedchemlett.4c00150

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title = "AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications",

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.",

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author = "Pippione, {Agnese C.} and Chiara Vigato and Cristina Tucciarello and Samrina Hussain and Edoardo Salladini and Truong, {Ha H.} and Henriksen, {Niel M.} and Gaia Vanzetti and Giorgia Giordano and Daniele Zonari and Mirza, {Osman Asghar} and Karla Frydenvang and Ymera Pignochino and Simonetta Oliaro-Bosso and Donatella Boschi and Lolli, {Marco L.}",

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AU - Vigato, Chiara

AU - Tucciarello, Cristina

AU - Hussain, Samrina

AU - Salladini, Edoardo

AU - Truong, Ha H.

AU - Henriksen, Niel M.

AU - Vanzetti, Gaia

AU - Giordano, Giorgia

AU - Zonari, Daniele

AU - Mirza, Osman Asghar

AU - Frydenvang, Karla

AU - Pignochino, Ymera

AU - Oliaro-Bosso, Simonetta

AU - Boschi, Donatella

AU - Lolli, Marco L.

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AB - 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.

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KW - Osteosarcoma

KW - Prostate Cancer

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