Recent advancements in the small-molecule drugs for hepatocellular carcinoma (HCC): Structure-activity relationships, pharmacological activities, and the clinical trials

• Published in: Biomedicine & pharmacotherapy 2024-10, Vol.179, p.117343, Article 117343
• Main Authors: Deng, Qichuan, Huang, Yu, Zeng, Jing, Li, Xinyu, Zheng, Xianyi, Guo, Li, Shi, Jianyou, Bai, Lan
• Format: Article
• Language: English
• Subjects: Hepatocellular Carcinoma; listed small-molecule drugs; structure-activity relationship; targeted therapy
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.117343

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and the sixth leading cause of cancer death worldwide, and it is urgent to find safe and effective drugs for treatment. As an important therapeutic method, small-molecule drugs are continually being updated to achieve improved therapeutic effects. The purpose of this study was to investigate the structural effects of various FDA-listed small-molecule drugs sorafenib, cabozantinib, lenvatinib, and regorafenib on the corresponding HCC targets and possible structural optimization methods, and to explore the mechanism for identifying potential therapeutic drugs that offer better efficacy and fewer side effects. The structure-activity relationship, pharmacological actions, and clinical applications of small-molecule drugs were reviewed by referencing MEDLINE, Web of Science, CNKI, and other databases, summarizing and integrating the relevant content. The results showed that small-molecule drugs can inhibit HCC primarily by forming hydrogen bonds with Glu885, Asp1046, and Cys919 on the HCC target. HCC can be targeted by inhibiting the activation of multiple pathways, blocking the conduction of downstream signaling, and reducing the formation of tumor blood vessels. In general, small-molecule drugs primarily target four key receptors in HCC: VEGFR, PDGFR, EGFR, and FGFR, to achieve effective treatment. By revealing their structure-activity relationships, pharmacological actions, and clinical trials, small-molecule drugs can offer broad prospects for the development of new medications. [Display omitted] •Small molecules for HCC: targeted structure-activity relationships.•Small-molecule mechanisms in HCC pharmacology.•Clinical trials of small molecules in HCC.•Combining small molecules for HCC: enhanced efficacy, minimized toxicity.