Small molecules targeting Pin1 as potent anticancer drugs

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Pin1, a peptidyl-prolyl isomerase (PPIase), regulates oncogenic pathways by inducing conformational changes in phosphorylated proteins.
• Inhibiting Pin1 offers a targeted strategy for disrupting cancer progression and developing novel anticancer therapies.

Purpose of the Study:

• To identify and characterize novel inhibitors of Pin1 using a high-throughput screening method.
• To evaluate the anticancer potential of identified compounds in vitro and in vivo.

Main Methods:

• High-throughput screening in budding yeast to identify Pin1 inhibitors.
• In vitro assays including enzyme activity, SPR, docking, proliferation, western blotting, cell cycle, apoptosis, migration assays.
• In vivo studies using nude mouse xenograft models.

Main Results:

• Compounds HWH8-33 and HWH8-36 inhibited Pin1 activity and cancer cell proliferation in vitro.
• These compounds induced G2/M phase arrest, apoptosis, and suppressed migration.
• HWH8-33 demonstrated in vivo anticancer activity in xenograft mice with no observed toxicity.

Conclusions:

• HWH8-33 and HWH8-36 are effective Pin1 inhibitors with demonstrated anticancer properties.
• These compounds represent promising candidates for further development into novel antitumor drugs.