TrkC-Targeted Kinase Inhibitors And PROTACs

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Tropomyosin receptor kinase C (TrkC) is implicated in various cancers, including breast cancer.
• Targeting TrkC presents a therapeutic strategy for cancer treatment.
• Developing targeted drug delivery systems and degradation strategies is crucial for effective cancer therapy.

Purpose of the Study:

• To investigate the use of a small molecule motif (IY-IY) for targeted delivery of dasatinib to TrkC-expressing breast cancer cells.
• To compare the efficacy of noncleavable and cleavable linkers in drug conjugates.
• To explore the potential of the IY-IY motif in developing proteolysis targeting chimeras (PROTACs) for TrkC degradation.

Main Methods:

• Synthesis of dasatinib conjugates with noncleavable (1) and cleavable (2) linkers, utilizing the IY-IY motif.
• Cellular assays to evaluate the impact of conjugates on cell viability in TrkC-positive and TrkC-negative breast cancer cells.
• Development and testing of a PROTAC utilizing the IY-IY motif for TrkC degradation.

Main Results:

• Conjugates demonstrated greater impact on the viability of TrkC-positive breast cancer cells compared to TrkC-negative epithelial cells.
• The IY-IY fragment successfully recruited the E3 ligase cereblon.
• A potent PROTAC was developed for TrkC degradation in metastatic breast cancer cells.

Conclusions:

• The IY-IY motif is effective for targeted delivery of kinase inhibitors to TrkC-expressing breast cancer.
• The developed PROTAC strategy offers a promising approach for TrkC degradation in metastatic breast cancer.