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Key Advantages of Chaperon Mediated Degrader
Several issues in developing classical PROTACs are recently reported in literature and clinical trials.
For example, classical PROTAC has limited E3 ligases only available and poor tumor selectivity, off-target effect, point of mutation and poor PK/PD effect etc.
On the other hand, HSP90 chaperon has a significantly higher binding affinity in tumor cells compared to normal cells so it could offer tumor selectivity, and the other advantage is favorable tumor pharmacokinetic / pharmacodynamic that is clinically validated by radio labelled PET experiment in human clinical trial.
Chaperon mediated degradation pathway might be less vulnerable in mutagenic resistance mechanism mainly due to multiple E3 ligases involved in the process of degradation.
For example, classical PROTAC has limited E3 ligases only available and poor tumor selectivity, off-target effect, point of mutation and poor PK/PD effect etc.
On the other hand, HSP90 chaperon has a significantly higher binding affinity in tumor cells compared to normal cells so it could offer tumor selectivity, and the other advantage is favorable tumor pharmacokinetic / pharmacodynamic that is clinically validated by radio labelled PET experiment in human clinical trial.
Chaperon mediated degradation pathway might be less vulnerable in mutagenic resistance mechanism mainly due to multiple E3 ligases involved in the process of degradation.
