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Deep learning enables the discovery of a novel cuproptosis-inducing molecule for the inhibition of hepatocellular carcinoma

Acta Pharmacologica Sinica volume 45, pages 391–404 (2024)Cite this article

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers in the world. The therapeutic outlook for HCC patients has significantly improved with the advent and development of systematic and targeted therapies such as sorafenib and lenvatinib; however, the rise of drug resistance and the high mortality rate necessitate the continuous discovery of effective targeting agents. To discover novel anti-HCC compounds, we first constructed a deep learning-based chemical representation model to screen more than 6 million compounds in the ZINC15 drug-like library. We successfully identified LGOd1 as a novel anticancer agent with a characteristic levoglucosenone (LGO) scaffold. The mechanistic studies revealed that LGOd1 treatment leads to HCC cell death by interfering with cellular copper homeostasis, which is similar to a recently reported copper-dependent cell death named cuproptosis. While the prototypical cuproptosis is brought on by copper ionophore-induced copper overload, mechanistic studies indicated that LGOd1 does not act as a copper ionophore, but most likely by interacting with the copper chaperone protein CCS, thus LGOd1 represents a potentially new class of compounds with unique cuproptosis-inducing property. In summary, our findings highlight the critical role of bioavailable copper in the regulation of cell death and represent a novel route of cuproptosis induction.

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Fig. 1: The discovery of novel drug-like compounds with growth inhibitory properties in liver cancer by deep learning.
Fig. 2: The in vitro and in vivo anti-liver cancer activities of LGOd1.
Fig. 3: LGOd1 induces ROS accumulation.
Fig. 4: LGOd1 induces down-regulation of Fe-S cluster proteins.
Fig. 5: LGOd1 induces cuproptosis in HCC cells and xenograft tumors.
Fig. 6: LGOd1 interferes with copper homeostasis but not acting as an ionophore.
Fig. 7: LGOd1 impairs copper homeostasis and induces cuproptosis by targeting CCS.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (32070748, 81902787); Excellent Scientific and Technological Innovation Training Program of Shenzhen (RCYX20210706092040048); Natural Science Foundation of Top Talent of SZTU (Grant No. GDRC202125); Singapore’s National Research Foundation (NRF‐CRP22‐2019‐0003).

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Author notes

  1. These authors contributed equally: Fan Yang, Lin Jia

Authors and Affiliations

  1. Department of Geriatrics, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People’s Hospital (the Second Clinical Medical College of Jinan University; the First Affiliated Hospital of Southern University of Science and Technology), Shenzhen, 518020, China

    Fan Yang, Hong-chao Zhou, Jing-nan Huang, Meng-yun Hou, Feng-ting Liu, Zhi-jie Li, Chuan-bin Yang, Chang Zou, Ji-gang Wang & Ling-yun Dai

  2. Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632, China

    Fan Yang

  3. College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, China

    Lin Jia

  4. Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore

    Nayana Prabhu, Pär Nordlund & Ling-yun Dai

  5. Department of Clinical Medical Research Center, The First Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, 518020, China

    Chang Zou

  6. Department of Oncology and Pathology, Karolinska Institutet, 17177, Stockholm, Sweden

    Pär Nordlund

  7. Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Ji-gang Wang

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  1. Fan Yang
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Contributions

Conceptualization: LYD; Methodology: LYD, JGW, PN, FY, NP; Investigation: FY, LJ, HCZ, JNH, MYH, ZJL, CZ, FTL; Visualization: FY, CBY; Supervision: LYD, JGW, PN; Writing—original draft: FY, LYD; Writing—review & editing: FY, LJ, JGW, LYD.

Corresponding authors

Correspondence to Ji-gang Wang or Ling-yun Dai.

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Competing interests

PN is the inventor of patents related to the CETSA method and is a cofounder and board member of Pelago Biosciences AB. LYD, JGW, FY, LJ, CBY, HCZ and MYH have a patent pending for compound LGOd1. The remaining authors declare they have no competing interests.

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Yang, F., Jia, L., Zhou, Hc. et al. Deep learning enables the discovery of a novel cuproptosis-inducing molecule for the inhibition of hepatocellular carcinoma. Acta Pharmacol Sin 45, 391–404 (2024). https://doi.org/10.1038/s41401-023-01167-7

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