Controlling cellular distribution of drugs with permeability modifying moieties

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Phenotypic screening yields compounds lacking crucial cellular localization data.
• Distinguishing cell-surface versus intracellular compound action is vital for target identification.
• Controlling cell permeability is key for targeted therapeutics to minimize off-target toxicity.

Purpose of the Study:

• To develop a strategy for modulating compound cell permeability.
• To correlate cellular activity with subcellular localization using modified compounds.
• To assess the utility of these modifications in target deconvolution and therapeutic delivery.

Main Methods:

• Incorporation of polar, anionic moieties via polyethylene glycol linkers into known intracellular and cell-surface targeting compounds.
• Evaluation of biological activity in cell-based assays before and after modification.
• Assessment of binding and activity changes for cell-surface targets.

Main Results:

• Compounds targeting intracellular (nuclear/cytosolic) sites lost significant biological activity upon modification.
• Compounds targeting cell-surface receptors maintained significant activity, though binding/activity were modulated.
• Small anionic compounds effectively controlled cell permeability independently of on-target activity.

Conclusions:

• Small anionic compounds can be strategically employed to control cell permeability.
• This approach aids in target deconvolution studies by differentiating cellular sites of action.
• The method offers potential for refining drug distribution and reducing toxicity in targeted therapeutics.