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

Abnormal activation of the YAP transcriptional signaling
pathway
drives proliferation in many hepatocellular carcinoma (HCC) and hepatoblastoma
(HB) cases. Current treatment options often face resistance and toxicity,
highlighting the need for alternative therapies. This article reports
the discovery of a hit compound C-3 from docking-based
virtual screening targeting TEAD lipid binding pocket, which inhibited
TEAD-mediated transcription. Optimization led to the identification
of a potent and covalent inhibitor CV-4-26 that exhibited
great antitumor activity in HCC and HB cell lines in vitro, xenografted
human HCC, and murine HB in vivo. These outcomes signify the potential
of a highly promising therapeutic candidate for addressing a subset
of HCC and HB cancers. In the cases of current treatment challenges
due to high upregulation of YAP-TEAD activity, these findings offer
a targeted alternative for more effective interventions against liver
cancer.

YAP转录信号通路的异常激活在多数肝细胞癌（hepatocellular carcinoma, HCC）与肝母细胞瘤（hepatoblastoma, HB）病例中可驱动肿瘤增殖。当前临床治疗方案常面临耐药性与毒性双重挑战，凸显了开发替代疗法的迫切需求。本文报道了一种通过基于分子对接的虚拟筛选靶向TEAD脂质结合口袋所获得的命中化合物C-3，该化合物能够有效抑制TEAD介导的转录过程。经结构优化后，研究人员鉴定出一种强效共价抑制剂CV-4-26，其在体外HCC与HB细胞系、体内异种移植的人HCC模型及小鼠HB模型中均展现出优异的抗肿瘤活性。上述研究成果表明，该候选药物有望成为针对特定亚型HCC与HB癌症的极具潜力的治疗方案。针对因YAP-TEAD活性高度上调而陷入当前治疗困境的病例，本研究为更高效的肝癌靶向干预提供了全新的可选策略。