Re-Evaluating PIN1 as a Therapeutic Target in Oncology Using Neutral Inhibitors and PROTACs

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) is a potential cancer therapeutic target.
• Existing PIN1 inhibitors exhibit limited efficacy in preclinical cancer models.
• The oncogenic role of PIN1 remains uncertain, necessitating further investigation.

Purpose of the Study:

• To identify and develop novel small-molecule inhibitors of PIN1.
• To evaluate the therapeutic potential of PIN1 inhibition in cancer.
• To explore alternative strategies like PROTACs for PIN1 targeting.

Main Methods:

• Screening of a DNA-encoded library (DEL) to identify novel PIN1 inhibitors.
• Chemical synthesis and optimization of identified lead compounds (A0, C10).
• Development of PIN1-targeted Proteolysis Targeting Chimeras (PROTACs).
• Assessment of antiproliferative activity and protein downregulation via siRNA.

Main Results:

• Novel nonacidic PIN1 inhibitors, including DEL1067-56-469 (A0) and optimized C10, were identified.
• Neither optimized inhibitors nor C10-based PROTACs demonstrated significant antiproliferation effects.
• siRNA-mediated PIN1 knockdown provided unfavorable evidence for its role as an oncologic target.

Conclusions:

• Targeting PIN1 with small molecules or PROTACs did not yield meaningful anticancer activity.
• The study suggests PIN1 may not be a viable oncologic target despite initial promise.
• Further research is needed to understand the complex role of PIN1 in cancer therapy.