2. Academic Validation
  3. Discovery and characterization of sulfonamide derivatives as transcriptional enhanced associate domain (TEAD) inhibitors: a novel approach for targeting hepatocellular carcinoma

Discovery and characterization of sulfonamide derivatives as transcriptional enhanced associate domain (TEAD) inhibitors: a novel approach for targeting hepatocellular carcinoma

  • Bioorg Chem. 2025 Aug 28:165:108911. doi: 10.1016/j.bioorg.2025.108911.
Yang Lu 1,  Jian Gao 2,  Jun Mo 2,  Qiuqiu Shi 2,  Yu Guo 2,  Haifeng Chen 2,  Linjie Li 2,  Jingyi Zhao 2,  Jinxin Che 2,  Jiankang Zhang 3,  Xiaowu Dong 4,  Haiyan Yang 5
Affiliations

Affiliations

  • 1 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, PR China.; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China.
  • 2 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China.
  • 3 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China. Electronic address: zhang_jk@hzcu.edu.cn.
  • 4 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, PR China.. Electronic address: dongxw@zju.edu.cn.
  • 5 Wenzhou Medical University, Wenzhou 325035, PR China; Zhejiang Cancer Hospital, Hangzhou 310022, PR China. Electronic address: yanghy@zjcc.org.cn.
PMID: 40913956 DOI: 10.1016/j.bioorg.2025.108911
Abstract

Transcriptional enhanced associate domain (TEAD), overexpressed in hepatocellular carcinoma (HCC) and inversely correlated to prognosis, has emerged as a promising target for HCC therapy. To date, no small-molecule inhibitors targeting TEAD have been reported for HCC treatment. In this study, a bioinformatic analysis has been performed and has demonstrated that TEAD is a promising target for therapeutic intervention in HCC. Then, a series of sulfonamide derivatives, discovered by virtual screening and structure optimization, were rigorously evaluated for their anti-proliferative effects across various HCC cell lines. Among these, compound C11 demonstrated exceptional efficacy in inhibiting HCC cell viability and exhibited favorable pharmacokinetic properties. Mechanistic studies revealed that C11 acts as a novel TEAD modulator, selectively downregulating TEAD-dependent downstream genes. These findings underscore C11's potential as a therapeutic agent and establish a new paradigm in TEAD-targeted strategies for HCC treatment.

Keywords

Hepatocellular carcinoma; Transcriptional enhanced associate domain; Virtual screening.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-178098
    TEAD抑制剂
    YAP
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