Photocaging of N-pyridinyl amide scaffold-based PIM inhibitors for spatiotemporal controlled anticancer bioactivity

Photocaging is an ideal way to enable spatiotemporal control over the release of bioactive compounds for cancer treatments. In this work, a series of photocaged N-pyridinyl amide scaffold-based PIM inhibitors were developed by rendering the amino group unable to bind to the Asp128/Glu171 sites of PIM kinase with a photoremovable protecting group (PPG). Upon light irradiation, our studies revealed the structure-dependent photouncaging efficiency and screened out the photocaged PIM inhibitor FD1024-PPG. Its spatiotemporally controlled bioactivity was confirmed by cell-based in-vitro assays and revealed that it exerts the antiproliferation and induction of cell apoptosis through inhibition of PIM kinase upon light irradiation. Furthermore, the spatiotemporal control over the in-vivo anticancer activity was demonstrated using zebrafish xenograft model.