Development of folate receptor targeting chimeras for cancer selective degradation of extracellular proteins

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Targeted protein degradation utilizes cellular machinery to remove specific proteins.
• Degrading intracellular proteins shows clinical benefits, with recent advances in lysosomal degradation of extracellular proteins.
• Selective degradation in disease-relevant cells remains a challenge for precision medicine.

Purpose of the Study:

• To develop an accessible platform for targeted degradation of extracellular proteins in cancer cells.
• To enhance precision medicine by selectively targeting cancer-related proteins.
• To create versatile chemical probes and therapeutics for cancer research and treatment.

Main Methods:

• Designed Folate Receptor TArgeting Chimeras (FRTACs) to recruit folate receptors.
• Utilized FRTACs to target extracellular soluble and membrane proteins in cancer cells.
• Evaluated FRTAC efficacy in vitro and in vivo.

Main Results:

• FRTACs successfully recruited folate receptors, primarily expressed on malignant cells.
• Demonstrated degradation of extracellular soluble and membrane cancer-related proteins.
• FRTACs proved effective both in vitro and in vivo.

Conclusions:

• FRTACs represent an easily accessible class of molecules for targeted protein degradation.
• This platform enables precise targeting of extracellular proteins in cancer cells.
• FRTACs offer a generalizable approach for developing novel cancer therapeutics and chemical probes.