Small Molecule–Degrader Conjugates: Evaluating the Structure–Activity Relationship of Linkers to Overcome In Vivo Barriers in PROTAC Delivery

Precise control of proteolysis on target cells is important
for
proteolysis-targeting chimeras (PROTAC) to minimize off-tissue toxicities.
Small-molecule ligand-guided PROTACs, namely, small molecule–degrader
conjugates (SMDCs), offer many advantages, but some flaws in the previous
designs, especially linker chemistry, cause a considerable defect
in pharmacokinetics, which impedes in vivo applications. Here, we
investigated the relationship of linker structures with in vivo factors,
including serum stability, blood retention, controlled PROTAC release,
targetability, and potency. Based on the structure–activity
relationship (SAR) study, the cathepsin-responsive/carbamate linker
bearing a long-circulating CBB protractor was developed to conjugate
the cRGD peptide and GNE-987 PROTAC. This peptide-drug conjugate showed
an excellent targeting capability, long-term stability, and favorable
pharmacokinetics, which enabled the selective proteolysis of targets
in an antigen-dependent manner and achieved a tumor growth arrest
in vivo by a dose much lower than regular SMDCs and free PROTACs.
Our results demonstrated that linker-optimized SMDC degraders can
be promising modalities in precision medicine.