PIN1 is a prolyl isomerase, which binds to several proteins, acts as a post phosphorylation control and regulates protein function. PIN1 targets proteins containing phosphorylated S/T-P sites firstly via the WW domain to bind to the protein. Next, the enzyme catalyzes the cis/trans isomerization via the catalytic PPIase domain. Overexpression of the enzyme occurs in certain cancers. PIN1 significantly enhances tumor initiation and expansion. Although the inactivation of PIN1 blocks tumor growth and progression, there is a shortage of PIN1 inhibitors for cancer therapy.

Herein, let’s discuss the effect of a PIN1 inhibitor, KPT-6566, on cancer research.

KPT-6566 covalently binds to PIN1 PPIase, and inhibits the PPIase activity of PIN1, with an IC₅₀ of 0.64 μM. It selectively inhibits PIN1 instead of other PPIases. KPT-6566 does not affect the PPIase activity of recombinant GST-FKBP4 and GST-PPIA, which also own cysteine residues.

In a further study, it proves that KPT-6566 affects PIN1 activity in cells. In wild-type mouse embryos (MEFs), KPT-6566 dose-dependently inhibits the proliferation. What’s more, KPT-6566 decreases pRB and Cyclin D1 hyperphosphorylation. On contrast, KPT-6566 has no effect on the proliferation and pRB and Cyclin D1 hyperphosphorylation in Pin1 knockout MEFs.

In addition, KPT-6566 down-regulates PIN1 substrates and their target genes. KPT-6566 also impairs PIN1-dependent oncogenic phenotypes. It induces PIN1 degradation and cellular stress responses. KPT-6566 causes DNA damage via PIN1 and induces cell death in cancer cells.

Besides, KPT-6566 exhibits significantly anti-tumor activity in nude mice via intraperitoneal injection at a dose of 5 mg/kg.