KPT-6566

**KPT-6566 is a small molecule covalent inhibitor of prolyl isomerase PIN1 (peptidyl-prolyl cis/trans isomerase, NIMA-interacting 1), developed to selectively target and degrade PIN1, a key regulator of oncogenic signaling in cancer cells.** KPT-6566 acts by covalently binding to the PIN1 active site, specifically targeting cysteine 113, thereby inhibiting PIN1’s peptidyl-prolyl isomerase activity and promoting its degradation[2][5][1][3]. This leads to widespread impairment of PIN1-dependent oncogenic phenotypes, including reduction of cyclin D1, c-JUN, MCL-1, NOTCH1 intracellular domain, and mutant p53, as well as inhibition of cancer cell proliferation, migration, invasion, and colony formation[2][5][1]. **KPT-6566 also induces cancer cell-specific cell death by generating reactive oxygen species (ROS) and causing DNA damage via a quinone-mimicking byproduct, resulting in both cytostatic and cytotoxic effects**[5][4][2]. It shows preferential activity in cancer cells over normal cells due to higher PIN1 expression and greater vulnerability to oxidative stress. In in vivo models, KPT-6566 suppresses tumor growth and metastasis in xenograft and lung colonization assays with manageable toxicity[2][5][4]. Primary indications under investigation are PIN1-dependent cancers, including breast, prostate, lung, pancreatic cancer, and testicular germ cell tumors[2][4][5][6]. **KPT-6566 is investigational and has not been approved for clinical use as of the latest available data.**