Discovery of a Small Molecule with an Inhibitory Role for RAB11

Area of Science:

• Biochemistry
• Cell Biology
• Drug Discovery

Background:

• RAB11, a RabGTPase, is crucial for cellular functions like endocytic recycling, exocytosis, and autophagy.
• Dysregulation of RAB11 is linked to various diseases, including cancer and neurodegenerative disorders.
• A lack of specific small-molecule inhibitors hinders research and therapeutic development for RAB11-associated conditions.

Purpose of the Study:

• To develop a method for identifying small-molecule inhibitors of RAB11 protein.
• To validate potential inhibitors through in vitro and in vivo models.

Main Methods:

• Utilized deep learning-based computational screening to identify potential RAB11 inhibitors.
• Employed an in vitro platform measuring GFP exocytosis to validate compound activity.
• Assessed compound effects on autophagy and Rab11 vesicle localization.
• Validated findings in *Drosophila* models, assessing toxicity and RAB11-dependent function.

Main Results:

• In silico screening identified 94 candidate compounds, with 9 validated in vitro for RAB11 activity.
• Three potent compounds were confirmed to modulate autophagy.
• Two compounds shifted Rab11 vesicles without affecting Rab5 or Rab7.
• *Drosophila* studies showed a candidate compound had low toxicity and inhibited RAB11-dependent nephrocyte function.

Conclusions:

• A combined computational and experimental approach successfully identified small molecules that modulate RAB11 function.
• These identified compounds represent promising leads for developing therapeutics for RAB11-related diseases.