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

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is frequently overexpressed or hyperactivated in various human cancers and plays a significant role in cancer development. Although Pin1 has long been considered a promising therapeutic target, effectively inhibiting its function has proven difficult. It is proposed that inhibiting only its enzymatic activity may not be enough to fully eliminate its function.

In this context, a new compound named P1D-34 has been identified as a first-of-its-kind and highly effective PROTAC-based degrader of Pin1. P1D-34 promotes Pin1 degradation with a DC50 of 177 nM and demonstrates strong anti-proliferative effects in several acute myeloid leukemia (AML) cell lines, effects that depend on protein degradation. In comparison, the Pin1 inhibitor Sulfopin did not produce similar results. Importantly, P1D-34 was found to enhance the sensitivity of AML cells resistant to the Bcl-2 inhibitor ABT-199, indicating its potential use in overcoming resistance to current therapies.

Mechanistic studies showed that P1D-34 treatment increases reactive oxygen species (ROS) activity while suppressing the unfolded protein response (UPR), leading to DNA damage and cell apoptosis. Additionally, combining P1D-34 with the glucose metabolism inhibitor 2-deoxy-D-glucose (2-DG) produced a synergistic anti-proliferative effect, broadening the scope of its therapeutic application.

These findings demonstrate the feasibility and value of using PROTAC technology to target Pin1, offering a promising strategy for the treatment of AML, particularly in cases that are resistant to existing therapies.