The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1’s active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Nevertheless, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a chemical probe suitable for assessment of Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.

肽基-脯氨酰异构酶 Pin1 在癌症中被利用来激活癌基因和灭活肿瘤抑制因子。然而，尽管付出了相当大的努力，Pin1 仍然是一个难以捉摸的药物靶点。在这里，我们筛选了一个亲电子片段库来识别针对 Pin1 活性位点 Cys113 的共价抑制剂，从而开发出一种纳摩尔级 Pin1 抑制剂 Sulfopin。经两种独立的化学蛋白质组学方法验证，Sulfopin 具有高度选择性，可实现有效的细胞和体内靶标接合以及表型 Pin1 基因敲除。Pin1 抑制对癌细胞系的活力只有适度的影响。然而，在 MYCN 驱动的神经母细胞瘤的小鼠和斑马鱼模型中，磺胺平诱导 c-Myc 靶基因的下调，减少肿瘤进展并赋予生存益处，在胰腺癌的小鼠模型中。我们的研究结果表明，Sulfopin 是一种化学探针，适用于评估细胞和体内的 Pin1 依赖性药理学，并且 Pin1 作为潜在的癌症药物靶点值得进一步研究。