Folate-Guided Protein Degradation by Immunomodulatory Imide Drug-Based Molecular Glues and Proteolysis Targeting Chimeras

Molecular
glues and proteolysis targeting chimeras (PROTACs) are
promising new therapeutic modalities. However, the lack of specificity
for molecular glue- or PROTAC-mediated proteolysis in cancer cells
versus normal cells raises potential toxicity concerns that will likely
limit their clinical applications. Here, we developed a general strategy
to deliver immunomodulatory imide drug (IMiD)-based molecular glues
and PROTACs to folate receptor α (FOLR1)-positive cancer cells.
Specifically, we designed a folate-caged pomalidomide prodrug, FA-S2-POMA,
by incorporating a folate group as a caging and guiding element and
validated its degradation effect on its neo-substrates in FOLR1-positive
cancer cells in a FOLR1-dependent manner. We also developed a folate-caged
pomalidomide-based anaplastic lymphoma kinase (ALK) PROTAC, FA-S2-MS4048,
which effectively degraded ALK fusion proteins in cancer cells, again
in a FOLR1-dependent manner. This novel approach provides a generalizable
platform for the targeted delivery of IMiD-based molecular glues and
PROTACs to FOLR1-expressing cancer cells with the potential to ameliorate
toxicity.