Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the...

Area of Science:

• Biochemistry
• Chemical Biology
• Cancer Biology

Background:

• Peptidyl-prolyl isomerase NIMA-interacting-1 (Pin1) is a crucial enzyme that regulates numerous cancer-driving pathways.
• Aberrant Pin1 activation is a common feature in many human cancers, making it a significant therapeutic target.

Purpose of the Study:

• To identify and develop novel, potent inhibitors of Pin1.
• To elucidate the binding mechanisms of these inhibitors with Pin1.
• To evaluate the efficacy of the developed inhibitors in cancer cells.

Main Methods:

• Screening of an in-house chemical library to identify hit compounds.
• Structure-guided optimization of lead compounds using crystallographic studies.
• Co-crystallization of Pin1 with inhibitors to determine binding modes.
• Cell-based assays to assess the biological activity of inhibitors.

Main Results:

• A novel hit compound, ZL-Pin01, was identified, covalently modifying Pin1 at Cys113.
• Structure-guided optimization yielded ZL-Pin13, a highly potent Pin1 inhibitor (IC50 = 0.067 ± 0.03 μM).
• Co-crystal structures revealed detailed binding interactions and inhibitor-induced conformational changes in Pin1 (e.g., Gln129).
• ZL-Pin13 demonstrated significant inhibition of proliferation and downregulation of Pin1 substrates in MDA-MB-231 cells.

Conclusions:

• ZL-Pin13 is a potent covalent inhibitor of Pin1 with potential therapeutic applications.
• The developed inhibitors and structural data provide valuable tools for further investigation of Pin1's functional roles in cancer.
• This study highlights the potential of targeting Pin1 for cancer therapy.