Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution
Andrew Potter1, Victoria Oldfield, Claire Nunns
1Vernalis (R&D) Ltd, Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom.
Abstract:
Pin1 is an emerging oncology target strongly implicated in Ras and ErbB2-mediated tumourigenesis. Pin1 isomerizes bonds linking phospho-serine/threonine moieties to proline enabling it to play a key role in proline-directed kinase signalling. Here we report a novel series of Pin1 inhibitors based on a phenyl imidazole acid core that contains sub-μM inhibitors. Compounds have been identified that block prostate cancer cell growth under conditions where Pin1 is essential.
Insights
Researchers developed new phenyl imidazole acid-based compounds that inhibit Pin1 (Peptidyl-prolyl cis-trans isomerase). These novel Pin1 inhibitors effectively block prostate cancer cell growth, offering a promising new avenue for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Pin1 (Peptidyl-prolyl cis-trans isomerase) is a key enzyme in proline-directed kinase signaling pathways.
- Pin1 plays a critical role in Ras and ErbB2-mediated tumor development.
- Understanding Pin1's role is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To discover and characterize novel inhibitors of Pin1.
- To evaluate the efficacy of these inhibitors in blocking cancer cell proliferation.
- To explore the therapeutic potential of Pin1 inhibition in prostate cancer.
Main Methods:
- Design and synthesis of a novel series of compounds based on a phenyl imidazole acid core.
- In vitro biochemical assays to determine inhibitory activity against Pin1.
- Cell-based assays to assess the impact of inhibitors on prostate cancer cell growth.
Main Results:
- Identification of sub-micromolar Pin1 inhibitors.
- Demonstration that these compounds effectively block prostate cancer cell growth.
- Confirmation that the observed anti-cancer effects are dependent on Pin1 activity.
Conclusions:
- The phenyl imidazole acid core represents a promising scaffold for developing potent Pin1 inhibitors.
- Novel Pin1 inhibitors show significant potential for treating prostate cancer.
- Targeting Pin1 offers a viable strategy for inhibiting tumor growth in specific cancer contexts.
