Proteolysis-targeting chimeras function by recruiting ubiquitin ligases to targeted intracellular proteins, which promotes the degradation of pathogenic proteins via the proteasome system. This has made many previously “undruggable” proteins into viable therapeutic targets. To date, dozens of proteolysis-targeting chimeras drugs have advanced to clinical trials. Among these, Vepdegestrant, a proteolysis-targeting chimera drug that targets the estrogen receptor (ER), recently released its Phase 3 clinical trial results and is expected to be approved for market soon.
Similar to proteolysis-targeting chimeras, scientists have also developed other technologies like lysosome-targeting chimeras (LYTACs) and autophagy-targeting chimeras (AUTACs). While proteolysis-targeting chimeras and AUTACs primarily target intracellular proteins, LYTACs generally focus on capturing and degrading secreted and membrane proteins, such as growth factors, disease-associated receptors, and cytokines. These proteins account for approximately 40% of the human proteome and are significant therapeutic targets for numerous diseases. However, the advancement of LYTACs has been met with considerable challenges, largely due to the limited diversity of available lysosomal transport receptors.
Recently, a research paper titled “Polyvalent folate receptor-targeting chimeras for degradation of membrane proteins” was published in Nature Chemical Biology, a subsidiary journal of Nature. The authors include Xinbo Zhou and Wu Zhong from the Academy of Military Medical Sciences, and Hongbin Deng from Peking Union Medical College, Chinese Academy of Medical Sciences.
The study identifies folate receptor α (FRα) as a new class of lysosomal transport receptor that facilitates the lysosomal degradation of membrane proteins. Based on this finding, the researchers developed a novel targeted protein degradation platform known as Folate Receptor-Targeting Chimera (FRTAC). This platform demonstrates high efficiency in targeting and degrading membrane proteins and shows significant promise for cancer therapy applications.
To create the FRTAC platform, the research team coupled multiple folate molecules to an antibody protein using a PEG1000 linker. Key features of the FRTAC mechanism include:
- FRTACs are selectively internalized by cancer cells that overexpress FRα.
- This process transports target proteins on the cell membrane to the lysosome for degradation.
- Simultaneously, FRα is released from the FRTAC and recycled back to the cell membrane.
- The optimized FRTAC shows sub-nanomolar potency in clearing cell membrane proteins, with its effectiveness dependent on FRα expression and lysosomal activity.
Using this platform, the team developed FR-Ctx to target EGFR and FR-Atz to target PD-L1. The results indicated that FR-Ctx inhibited the proliferation of cancer cells, while FR-Atz boosted T-cell-mediated cytotoxicity against tumor cells.
Furthermore, FR-Atz showed potent in vivo targeted degradation of PD-L1 in both a prostate cancer mouse model and a humanized melanoma mouse model. It triggered a tumor-specific immune response by reprogramming the tumor microenvironment from an immunosuppressive state to an immunostimulatory one, exhibiting therapeutic effects superior to those of traditional antibody drugs.
In summary, the research demonstrates that FRTACs can target tumor sites, achieve high affinity through crosslinking with FRα, and degrade various membrane proteins—including EGFR, TROP2, PD-L1, and HER2—with sub-nanomolar activity, highlighting their promising potential in cancer treatment.
Creative Biolabs provides comprehensive, custom services for targeted protein degradation (TPD), a cutting-edge therapeutic modality designed to eliminate disease-causing proteins. A critical component of this service is our specialized ligand design, which focuses on developing high-affinity, specific ligands for your protein of interest. Our expert team leverages advanced platforms and extensive experience to design potent ligands across a wide array of protein classes.
Our Ligand Design for Target Protein services include, but are not limited to, the following key areas:
- Targeting nuclear receptors (e.g. AR, ER, RAR)
- Targeting protein kinases (e.g. Akt, BCR, c-Abl, BTK, ALK, CDK9, RIPK2, DAPK1, PSD-95)
- Targeting transcriptional regulatory proteins (e.g. BRD4, Sirt2, HDAC6, TRIM24, IKZF1/3, Smad3)
- Targeting regulatory proteins (e.g. CRABP-I/II, TACC3, AHR, FKBP12, ERRα, X-protein)
- Targeting neurodegenerative related proteins (e.g. Huntingtin, Tau, α-synuclein)
- Targeting cellular metabolic enzymes (e.g. MetAP-2, DHODH)
Reference
Xiao, Dian, et al. “Polyvalent folate receptor-targeting chimeras for degradation of membrane proteins.” Nature chemical biology (2025): 1-11.