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

Yang, Fan1,2,3,4; Jia, Lin5; Zhou, Hong-chao1,2,3; Huang, Jing-nan1,2,3; Hou, Meng-yun1,2,3; Liu, Feng-ting1,2,3; Prabhu, Nayana6; Li, Zhi-jie1,2,3; Yang, Chuan-bin1,2,3; Zou, Chang1,2,3,7; Nordlund, Paer6,8; Wang, Ji-gang1,2,3,9,10; Dai, Ling-yun1,2,3,6

2023-10-01

10.1038/s41401-023-01167-7

ACTA PHARMACOLOGICA SINICA   Impact Factor & Quartile

1671-4083

1745-7254

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.

hepatocellular carcinoma cuproptosis deep learning levoglucosenone copper homeostasis cell death

SCI

English

Corresponding

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 (Gran["32070748","81902787"] ; National Natural Science Foundation of China[RCYX20210706092040048] ; Excellent Scientific and Technological Innovation Training Program of Shenzhen[GDRC202125] ; Natural Science Foundation of Top Talent of SZTU[NRF-CRP22-2019-0003]

Chemistry ; Pharmacology & Pharmacy

Chemistry, Multidisciplinary ; Pharmacology & Pharmacy

WOS:001081779500003

NATURE PUBL GROUP

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.Jinan Univ, Dept Geriatr, Shenzhen Peoples Hosp, Clin Med Coll 2, Shenzhen 518020, Peoples R China
2.Jinan Univ, Shenzhen Peoples Hosp, Clin Med Coll 2, Shenzhen Clin Res Ctr Geriatr, Shenzhen 518020, Peoples R China
3.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Peoples R China
4.Jinan Univ, Integrated Chinese & Western Med Postdoctoral Res, Guangzhou 510632, Peoples R China
5.Shenzhen Technol Univ, Coll Pharm, Shenzhen 518118, Peoples R China
6.ASTAR, Inst Mol & Cell Biol, Singapore, Singapore
7.Southern Univ Sci & Technol, Affiliated Hosp 1, Dept Clin Med Res Ctr, Sch Med, Shenzhen 518020, Peoples R China
8.Karolinska Inst, Dept Oncol & Pathol, S-17177 Stockholm, Sweden
9.China Acad Chinese Med Sci, Artemisinin Res Ctr, Beijing 100700, Peoples R China
10.China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing 100700, Peoples R China

Yang, Fan,Jia, Lin,Zhou, Hong-chao,et al. Deep learning enables the discovery of a novel cuproptosis-inducing molecule for the inhibition of hepatocellular carcinoma[J]. ACTA PHARMACOLOGICA SINICA,2023.

Yang, Fan.,Jia, Lin.,Zhou, Hong-chao.,Huang, Jing-nan.,Hou, Meng-yun.,...&Dai, Ling-yun.(2023).Deep learning enables the discovery of a novel cuproptosis-inducing molecule for the inhibition of hepatocellular carcinoma.ACTA PHARMACOLOGICA SINICA.

Yang, Fan,et al."Deep learning enables the discovery of a novel cuproptosis-inducing molecule for the inhibition of hepatocellular carcinoma".ACTA PHARMACOLOGICA SINICA (2023).