Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting porcupine may block the Wnt pathway which is often dysregulated in various cancers. Consequently porcupine inhibitors are thought to be promising oncology therapeutics. A high throughput screen against porcupine revealed several potent hits that were confirmed to be Wnt pathway inhibitors in secondary assays. We developed a pharmacophore model and used the putative bioactive conformation of a xanthine inhibitor for scaffold hopping. The resulting maleimide scaffold was optimized to subnanomolar potency while retaining good physical druglike properties. A preclinical development candidate was selected for which extensive in vitro and in vivo profiling is reported.

中文翻译：

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支架跳跃和马来酰亚胺基豪猪抑制剂的优化

豪猪是一种O-酰基转移酶，可调节Wnt分泌。抑制豪猪可能会阻断Wnt途径，而Wnt途径在各种癌症中常常失调。因此，豪猪抑制剂被认为是有前途的肿瘤治疗剂。针对豪猪的高通量筛选显示，在二级测定中证实了数个有效的命中点，这些命中点被证实是Wnt途径抑制剂。我们开发了一个药效团模型，并使用了黄嘌呤抑制剂的假定生物活性构象用于支架跳跃。将所得的马来酰亚胺支架优化至亚纳摩尔效价，同时保留良好的药物性质。选择了临床前开发候选物，据报道该候选物具有广泛的体外和体内分析。