Development of Novel Indole-Based Covalent Inhibitors of TEAD as Potential Antiliver Cancer Agents,Journal of Medicinal Chemistry

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Development of Novel Indole-Based Covalent Inhibitors of TEAD as Potential Antiliver Cancer Agents
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-13 , DOI: 10.1021/acs.jmedchem.4c00925
Chen Zhou ₁ , Chunbao Sun ₂ , Wei Zhou ₃ , Tian Tian ₂ , Daniel C Schultz ₁ , Tong Wu ₂ , Mu Yu _{4,

5} , Lizi Wu _{4,

5,

6} , Liya Pi ₂ , Chenglong Li _{1,

3,

7}

Affiliation

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.

中文翻译：

开发基于吲哚的 TEAD 共价抑制剂作为潜在的抗肝癌药物

YAP 转录信号通路的异常激活驱动许多肝细胞癌（HCC）和肝母细胞瘤（HB）病例的增殖。目前的治疗方案经常面临耐药性和毒性，这凸显了替代疗法的必要性。本文报道了从靶向 TEAD 脂质结合口袋的基于对接的虚拟筛选中发现的命中化合物 C-3，该化合物抑制了 TEAD 介导的转录。优化导致鉴定出一种有效的共价抑制剂 CV-4-26，它在体外 HCC 和 HB 细胞系、异种移植人 HCC 和小鼠 HB 体内表现出强大的抗肿瘤活性。这些结果表明了一种极具前景的候选治疗药物在治疗 HCC 和 HB 癌症方面的潜力。在 YAP-TEAD 活性高度上调导致当前治疗挑战的情况下，这些发现为更有效的肝癌干预措施提供了有针对性的替代方案。

更新日期：2024-09-13

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