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
Department of Science and Drug Technology, University of Turin, via Pietro Giuria 9, 10125 Turin, Italy.
Candiolo Cancer Institute, FPO-IRCCS, str. Prov 142 km 3.95, 10060 Candiolo, Turin, Italy.
ACS Med Chem Lett. 2024 Jul 3;15(8):1269-1278. doi: 10.1021/acsmedchemlett.4c00150. eCollection 2024 Aug 8.
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 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 determined a significantly increased activity of abiraterone, a drug approved for advanced prostate cancer. Compound 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.
醛酮还原酶1C3（AKR1C3）是前列腺癌和其他癌症中一种上调的酶；除了调节激素合成外，这种酶还被认为在肿瘤的侵袭性和药物抵抗中发挥作用。我们在此使用一种无偏向性方法来发现新的强效AKR1C3抑制剂：通过基于人工智能的虚拟药物筛选，化合物被鉴定为一种强效且选择性的酶抑制剂，能够在22RV1前列腺癌细胞模型中将这种活性转化为显著的抗增殖作用。与其他已知的AKR1C3抑制剂一样，化合物使阿比特龙（一种被批准用于晚期前列腺癌的药物）的活性显著增加。化合物在骨肉瘤细胞系中还与多柔比星显示出协同作用；具体而言，这种作用与AKR1C3表达相关。因此，在这项研究工作中，人工智能的使用使得能够鉴定出一种作为AKR1C3抑制剂的新结构及其增强化疗效果的潜力。
