Discovery of potent PROTAC degraders of Pin1 for the treatment of acute myeloid leukemia

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) is overexpressed and/or overactivated in many human cancers and has been shown to play a critical role during oncogenesis. Despite the potential of PIN1 as a drug target, its successful targeting has proved to be challenging. We speculate that only blocking the enzymatic function of PIN1 with inhibitors may not be sufficient to lead to a total loss-of-function. Here, we report the discovery of P1D-34, a first-in-class and potent PROTAC degrader of PIN1, which induced PIN1 degradation with a DC₅₀ value of 177 nM and exhibited potent degradation-dependent anti-proliferative activities in a panel of acute myeloid leukemia (AML) cell lines. In contrast, PIN1 Inhibitor Sulfopin did not show activity. More significantly, P1D-34 could sensitize Bcl-2 Inhibitor ABT-199 in Bcl-2 inhibitor-resistant AML cells, highlighting the potential therapeutic value of targeted PIN1 degradation for Bcl-2 inhibitor-resistant AML treatment. Further mechanism study revealed that P1D-34 led to the up-regulation of ROS pathway and down-regulation of UPR pathway to induce cell DNA damage and Apoptosis. Notably, we further demonstrated that treatment with the combination formula of glucose metabolism inhibitor 2-DG and P1D-34 led to a notable synergistic anti-proliferative effect, further expanding its applicability. These data clearly reveal the practicality and importance of PROTAC as a preliminary tool compound suitable for assessment of Pin1-dependent pharmacology and a promising strategy for AML treatment.