Targeting WWPI HECT Domain by Small Inhibitors for Restoring PTEN Tumor Suppressive Role in Glioblastoma Therapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• PTEN is a crucial tumor suppressor frequently inactivated in glioblastoma.
• E3 ligases targeting WWPI HECT domain inactivate PTEN, promoting cancer progression.
• Restoring PTEN activity is a key therapeutic goal for glioblastoma.

Purpose of the Study:

• To identify novel inhibitors of the WWPI HECT domain.
• To explore therapeutic strategies for glioblastoma by targeting PTEN inactivation.
• To computationally screen compounds for WWPI HECT domain inhibition.

Main Methods:

• Virtual screening of approximately 960 compounds against the WWPI HECT domain active pocket.
• Selection of 15 compounds based on favorable binding affinities and docking scores.
• In vitro anti-proliferative assays using U87 glioma cell line.

Main Results:

• Five compounds (C5, C6, C8, C9, C11) showed favorable drug-like properties.
• Compounds C5, C6, C8, C9, and C11 demonstrated significant anti-proliferative effects on U87 glioma cells.
• IC50 values ranged from 6.98 ± 0.14 μM (C5) to 18 ± 1.23 μM (C11).

Conclusions:

• Compounds C5 and C8 exhibited potent inhibitory activity against glioma cells.
• The identified compounds may restore PTEN tumor suppressive functions.
• Targeting the WWPI HECT domain presents a promising therapeutic avenue for glioblastoma.