Pin1 regulates the function and stability of specific phosphoproteins by catalyzing the cis/trans isomerization of peptidyl-prolyl bonds that follow phosphorylated serine or threonine residues, and is frequently overexpressed in cancer. In triple-negative breast cancer (TNBC), Pin1 mediates oncogenic signaling networks to drive the epithelial-mesenchymal transition (EMT) and cell migration, suggesting that Pin1 inhibition could address the critical need for targeted TNBC therapy. However, despite previous efforts, there are currently no Pin1 inhibitors that can serve as informative cellular probes. The goal of this research program is to develop the first covalent Pin1 inhibitors with the requisite potency, selectivity, and cell permeability to interrogate the potential of Pin1 as a therapeutic target in TNBC.
The first aim i s to synthesize linear and macrocyclic peptidomimetic inhibitors of Pin1 that act via the formation of a covalent adduct with a critical cysteine residue, Cys113, in the Pin1 active site. Such covalent inhibitors would overcome the limitations of existing Pin1 inhibitors by achieving added specificity and longer lasting biochemical effects. In the second aim, these inhibitors will be characterized with respect to their cellular target engagement, anti-proliferative effects, and effects on EMT and cell migration in TNBC. This proposal therefore offers the first Pin1 inhibitors with the required selectivity and potency to be used as cellular probes to study Pin1 biology, and contributes to the growing body of evidence for Pin1 inhibition as a treatment option for TNBC.
The peptidyl-prolyl isomerase, Pin1, regulates the structure and activity of specific proteins by isomerizing phosphorylated Ser/Thr-Pro bonds. Pin1 is frequently overexpressed in triple-negative breast cancer (TNBC) and promotes cell transformation by stabilizing oncogenes and inactivating tumor suppressors, as well as by driving the epithelial-mesenchymal transition (EMT). This proposal has important public health applications because it offers the first potent, selective, and cell permeable covalent Pin1 inhibitors, which will not only serve as useful tool compounds with which to study Pin1 biology, but also will inform the design of future targeted therapies for TNBC.
