July 8, 2025

LYTAC and PROTAC modalities set out to accomplish one thing: cause the degradation of a target protein. However, LYTAC and PROTAC modalities go about it in different ways.

PROTACs (PROteolysis TArgeting Chimeras), also called degraders, are small molecule modalities that link a target protein to an E3 ligase. Once linked, the E3 ligase transfers ubiquitin onto the target protein. The target protein tagged with ubiquitin becomes recognizable by a proteasome, which then degrades the target protein.

A PROTAC molecule can be leveraged in a therapeutic strategy to degrade a target protein that is linked to a disease. However, the location of the target protein is important. PROTACs can only target proteins that are inside cells (intracellular proteins). Arvinas has several PROTACs in the clinic, including Vepdegestrant (ARV-471). Vepdegestrant is being investigated in ER+ (estrogen receptor) breast cancer. Importantly, the targeted estrogen receptors are located inside cells.

But, what about target proteins located outside of cells? Those that are linked to neurological diseases?

LYTACs (LYsosome-TArgeting Chimeras) have the potential to target proteins found outside of cells. Because PROTACs leverage the ubiquitin-proteasome pathway, they are limited to targeting proteins that are found inside cells. LYTACs function by leveraging lysosomal proteolysis, mainly through receptor-mediated endocytosis. A LYTAC molecule binds to a target protein (located outside of a cell) and the LYTAC molecule also binds to a cell receptor that induces endocytosis. Once bound to the receptor, the LYTAC molecule and the target protein are engulfed by the cell and sent to a lysosome for degradation. Thus, LYTACs can target proteins found outside of cells for degradation.

LYTACs may be leveraged in diseases and disorders known to be associated with misfolded, mutated, or dysfunctional proteins found outside of cells. For example, prion diseases, Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis (ALS).

However, the development of LYTACs lags behind the advancement of PROTACs. A LYTAC molecule has not yet entered the clinic. Whether LYTACs gain attention and investment as a serious modality for treating diseases and disorders linked to dysfunctional extracellular proteins remains unknown.

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