Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is commonly overexpressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). While Pin1 is dispensable for viability in mice, it is required for activated Ras to induce tumorigenesis, suggesting a role for Pin1 inhibitors in Ras-driven tumors, such as PDAC. We report the development of rationally designed peptide inhibitors that covalently target Cys113, a highly conserved cysteine located in the Pin1 active site. The inhibitors were iteratively optimized for potency, selectivity and cell permeability to give BJP-06-005-3, a versatile tool compound with which to probe Pin1 biology and interrogate its role in cancer. In parallel to inhibitor development, we employed genetic and chemical-genetic strategies to assess the consequences of Pin1 loss in human PDAC cell lines. We demonstrate that Pin1 cooperates with mutant KRAS to promote transformation in PDAC, and that Pin1 inhibition impairs cell viability over time in PDAC cell lines.

肽基脯氨酰顺/反异构酶NIMA-interacting 1（Pin1）通常在人类癌症（包括胰腺导管腺癌（PDAC））中过表达。虽然Pin1对于小鼠的生存力是必不可少的，但激活Ras诱导肿瘤发生是必需的，这表明Pin1抑制剂在Ras驱动的肿瘤（例如PDAC）中的作用。我们报告开发合理设计的肽抑制剂，共价靶向Cys113，Cys113，位于Pin1活性位点的高度保守的半胱氨酸。对抑制剂的功效，选择性和细胞通透性进行了迭代优化，以提供BJP-06-005-3，这是一种多功能的工具化合物，可用来探测Pin1生物学并探究其在癌症中的作用。在抑制剂开发的同时，我们采用了遗传和化学遗传学策略来评估人PDAC细胞系中Pin1丢失的后果。