2. Academic Validation
  3. Discovery and optimization of novel TEAD inhibitors for in vivo investigation against hepatocellular carcinoma

Discovery and optimization of novel TEAD inhibitors for in vivo investigation against hepatocellular carcinoma

  • Eur J Med Chem. 2026 Sep 5:313:118886. doi: 10.1016/j.ejmech.2026.118886.
Dounan Xu 1,  Wenxi Su 2,  Yuhui Miao 3,  Xiaolin Luo 4,  Yipan Luo 5,  Shuang Hu 3,  Yongpeng Wang 6,  Chujiao Hu 7,  Cheng Luo 8,  Guangming Li 9,  Yuanyuan Zhang 10,  Shijie Chen 11,  Huan Xiong 12
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China.
  • 2 Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.
  • 5 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 7 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Key Laboratory of Innovation and Manufacturing for Pharmaceuticals, Guizhou Medical University, Guiyang, 550004, China.
  • 8 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China; State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Key Laboratory of Innovation and Manufacturing for Pharmaceuticals, Guizhou Medical University, Guiyang, 550004, China.
  • 9 Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai, 200092, China. Electronic address: [email protected].
  • 10 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: [email protected].
  • 11 Innovation Center for AI and Drug Discovery, School of Pharmacy, East China Normal University, Shanghai, 200062, China. Electronic address: [email protected].
  • 12 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China. Electronic address: [email protected].
PMID: 42068639 DOI: 10.1016/j.ejmech.2026.118886
Abstract

The overexpression of the transcriptional enhanced associate domain (TEAD), which regulates gene transcription linked to cell growth, drives the proliferation in cases of hepatocellular carcinoma (HCC). In order to discover novel TEAD inhibitors that are more effective and have better efficacy and pharmacokinetic properties for treating HCC, this study employed a cyclization strategy to generate a novel indole-based scaffold of TEAD inhibitors. A comprehensive and systematic structure-activity relationship (SAR) analysis identified the most promising compound: LC-TD-05, a non-covalent, partial TEAD Inhibitor with selective activity against TEAD1, TEAD2 and TEAD4, but reduced potency against TEAD3. LC-TD-05 exhibits good potency against TEAD1/2/4 (TEAD1 IC50 = 116.6 ± 21.7 nM, TEAD2 IC50 = 168.7 ± 17.1 nM, TEAD4 IC50 = 68.3 ± 18.2 nM), demonstrates favorable oral bioavailability (F = 53.7%), and exhibits significant anti-tumor activity in HCC LM3 models in vitro (LM3 cell IC50 = 248 ± 27.9 nM) and in vivo (TGI = 75%). Overall, this study provides a novel scaffold for TEAD inhibitors, enabling more effective interventions against HCC.

Keywords

Cyclization strategy; Hepatocellular carcinoma; Hippo pathway; Non-covalent inhibitor; Structure-activity relationship; TEAD.

Figures
Products