Wnt/β-catenin signaling pathway is a classical and crucial oncogenic pathway in many carcinomas, and Porcupine (PORCN) is an O-acyltransferase, which is indispensable and highly specific for catalyzing palmitoylation of Wnt ligands and facilitating their secretion and biofunction. Targeting PORCN provides a promising approach to specifically cure Wnt-driven cancers from the root. In this study, we designed series of pyridonyl acetamide compounds, and discovered a novel PORCN inhibitor WHN-88 with a unique di-iodinated pyridone structural fragment, which is significantly different from the reported inhibitors. We demonstrated that WHN-88 effectively abolished palmitoylation of Wnt ligands and prevented their secretion and the subsequent Wnt/β-catenin signaling transduction. Further experiments showed that, at well-tolerated doses, WHN-88 remarkably suppressed the spontaneous occurrence and growth of MMTV-Wnt1 murine breast tumors. Consistently, WHN-88 also notably restrained the progress of xenografted Wnt-driven human tumors, including PA-1 teratocarcinoma with high autocrine Wnt signaling and Aspc-1 pancreatic carcinoma with Wnt-sensitizing RNF43 mutation. Additionally, we disclosed that WHN-88 inhibited cancer cell stemness obviously. Together, we verified WHN-88 is a novel PORCN inhibitor with potent efficacy against the Wnt-driven cancers. Our findings enriched the structural types of PORCN inhibitors, and facilitated the development and application of PORCN inhibiting therapy in clinic.

Wnt/β-catenin 信号通路是许多癌症中经典且关键的致癌通路，而 Porcupine (PORCN) 是一种 O-酰基转移酶，对于催化 Wnt 配体的棕榈酰化并促进其分泌和生物功能是不可或缺且高度特异性的。靶向 PORCN 提供了一种从根本上特异性治愈 Wnt 驱动的癌症的有前途的方法。在本研究中，我们设计了一系列吡啶酮基乙酰胺化合物，发现了一种新型 PORCN 抑制剂 WHN-88，其具有独特的二碘化吡啶酮结构片段，与报道的抑制剂有显着差异。我们证明 WHN-88 有效地消除了 Wnt 配体的棕榈酰化并阻止了它们的分泌和随后的 Wnt/β-catenin 信号转导。进一步的实验表明，在耐受性良好的剂量下，WHN-88 显着抑制了 MMTV-Wnt1 小鼠乳腺肿瘤的自发发生和生长。一致地，WHN-88 还显着抑制了 Wnt 驱动的异种移植人类肿瘤的进展，包括具有高自分泌 Wnt 信号传导的 PA-1 畸胎癌和具有 Wnt 敏感性 RNF43 突变的 Aspc-1 胰腺癌。此外，我们还披露了 WHN-88 明显抑制癌细胞干性。我们一起验证了 WHN-88 是一种新型 PORCN 抑制剂，对 Wnt 驱动的癌症具有有效的疗效。我们的研究结果丰富了 PORCN 抑制剂的结构类型，促进了 PORCN 抑制疗法的开发和临床应用。包括具有高自分泌 Wnt 信号传导的 PA-1 畸胎癌和具有 Wnt 敏感性 RNF43 突变的 Aspc-1 胰腺癌。此外，我们还披露了 WHN-88 明显抑制癌细胞干性。我们一起验证了 WHN-88 是一种新型 PORCN 抑制剂，对 Wnt 驱动的癌症具有有效的疗效。我们的研究结果丰富了 PORCN 抑制剂的结构类型，促进了 PORCN 抑制疗法的开发和临床应用。包括具有高自分泌 Wnt 信号传导的 PA-1 畸胎癌和具有 Wnt 敏感性 RNF43 突变的 Aspc-1 胰腺癌。此外，我们还披露了 WHN-88 明显抑制癌细胞干性。我们一起验证了 WHN-88 是一种新型 PORCN 抑制剂，对 Wnt 驱动的癌症具有有效的疗效。我们的研究结果丰富了 PORCN 抑制剂的结构类型，促进了 PORCN 抑制疗法的开发和临床应用。