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A Novel Strategy to Block Mitotic Progression for Target Therapy
Northwestern University
Protein
Oncology
Hit To Lead or Lead Optimization
• Blockade of mitotic progression is an ideal approach to induce mitotic catastrophe that sup- presses cancer cell expansion. Cdc20 is a critical mitotic factor governing anaphase initiation and the exit from mitosis through recruiting substrates to APC/C for degradation.
• Inventors designed a proteolysis targeting chimera, called CP5V, which comprises a Cdc20 ligand and VHL binding moiety bridged by a PEG5 linker that induces Cdc20 degradation. Inventors characterized the effect of CP5V in destroying Cdc20, arresting mitosis, and inhibiting tumor progression by measuring protein degradation, 3D structure dynamics, cell cycle control, tumor cell killing and tumor inhibition using human breast cancer xenograft mouse model.
• CP5V can specifically degrade Cdc20 by linking Cdc20 to the VHL/VBC complex for ubiquitination followed by proteasomal degradation. Induced degradation of Cdc20 by CP5V leads to significant inhibition of breast cancer cell proliferation and resensitization of Taxol-resistant cell lines. Results based on a human breast cancer xenograft mouse model show a significant role for CP5V in suppressing breast tumor progression.
• CP5V-mediated degradation of Cdc20 could be an effective therapeutic strategy for anti- mitotic therapy.
US20220241424A1
A novel strategy to block mitotic progression for targeted therapy. EBioMedicine. (2019)
