A proteolysis targeting chimera (PROTAC) is a heterobifunctional molecule containing two small molecule-binding ligands joined together by a linker.
One of the small molecule ligands is designed to bind a disease target protein in the cell whilst the other binds with high affinity to an E3 ligase. In the cell, the PROTAC molecule seeks out and selectively binds to the disease target protein of interest and is then able to recruit a specific E3 ligase to form a ternary complex, holding both the disease target protein and the E3 ligase in close proximity. The E3 ligase then recruits an E2 conjugating enzyme to the ternary complex which is subsequently able to ubiquitinate the target protein. The E3 ligase can then recruit additional E2 molecules resulting in poly-ubiquitination of the target protein and flagging it for degradation. The PROTAC molecule dissociates from the target protein and initiates another cycle leaving the poly-ubiquitinated target protein to be degraded by the proteasome. This unique mode of action, which leads to depletion of disease target proteins from the cell, can drive distinct changes in cellular activity.
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