Emerging cellular uptake mechanisms of bRo5 PROTACs

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Proteolysis-targeting chimeras (PROTACs) often possess properties exceeding traditional drug permeability rules (beyond-rule-of-5 or bRo5).
• Classical models of passive membrane diffusion do not fully explain the cellular uptake of all bRo5 PROTACs, especially large and polar molecules.
• Factors like conformational flexibility, hydrogen bonding, and lipophilicity influence bRo5 compound permeability but don't account for all observed intracellular activity.

Purpose of the Study:

• To critically examine emerging cellular uptake mechanisms for bRo5 PROTACs.
• To evaluate the biological plausibility of receptor-mediated endocytosis, focusing on CD36, as a PROTAC uptake pathway.
• To distinguish experimentally supported findings from mechanistic hypotheses regarding PROTAC permeability.

Main Methods:

• Literature review and critical analysis of existing studies on PROTAC permeability.
• Evaluation of established permeability models in the context of bRo5 compounds.
• Assessment of CD36's role in lipid uptake and its potential relevance to PROTAC endocytosis.

Main Results:

• While passive diffusion and physicochemical properties contribute to bRo5 PROTAC uptake, they are insufficient to explain all cases.
• Emerging evidence suggests receptor-mediated endocytosis, specifically CD36-mediated endocytosis, may facilitate the uptake of certain bRo5 PROTACs (e.g., SIM1-Me, MZ1).
• CD36-mediated endocytosis is proposed as a context-dependent, complementary pathway, not a universal mechanism for all bRo5 PROTACs.

Conclusions:

• CD36-mediated endocytosis is a plausible, albeit context-dependent, mechanism for cellular uptake of specific bRo5 PROTACs.
• PROTAC structural features enabling receptor engagement are critical for this pathway's operation.
• Further research is needed to determine the generality of these uptake mechanisms and their implications for PROTAC design.