Development of Novel Indole-Based Covalent Inhibitors of TEAD as Potential Antiliver Cancer Agents

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The YAP transcriptional signaling pathway is abnormally activated in many hepatocellular carcinoma (HCC) and hepatoblastoma (HB) cases, driving tumor proliferation.
• Existing therapies for HCC and HB often encounter resistance and toxicity, necessitating the development of alternative treatment strategies.

Purpose of the Study:

• To identify novel therapeutic agents targeting the YAP-TEAD pathway for liver cancer treatment.
• To evaluate the efficacy of a newly developed covalent inhibitor, CV-4-26, against HCC and HB.

Main Methods:

• Docking-based virtual screening was employed to identify a hit compound (C-3) targeting the TEAD lipid-binding pocket.
• Compound C-3 was optimized to yield a potent, covalent inhibitor, CV-4-26.
• In vitro and in vivo studies assessed the antitumor activity of CV-4-26 in HCC and HB models.

Main Results:

• The optimized inhibitor CV-4-26 demonstrated significant antitumor activity in HCC and HB cell lines.
• CV-4-26 showed efficacy in xenografted human HCC and murine HB models.
• The compound effectively inhibited TEAD-mediated transcription, confirming pathway engagement.

Conclusions:

• CV-4-26 represents a promising therapeutic candidate for a subset of HCC and HB cancers.
• Targeting the YAP-TEAD pathway with CV-4-26 offers a potential alternative to overcome current treatment challenges in liver cancer.
• These findings support the development of targeted interventions for YAP-TEAD-driven liver malignancies.