Pharmaceutical Discovery and Preclinical Development1

PROTACs (Proteolysis-Targeting Chimeras) are considered  as a promising new approach for targeting previously 'undruggable' proteins, with growing interest in their clinical and preclinical applications across various disease indications. During the preclinical stages, what strategies or approaches can be employed to enhance the selectivity and specificity of PROTACs to minimize off-target protein degradation while maintaining efficacy? You may input from your own experiences. Thank you.

This is a hot topic. The choice of Linker has a role to play in the entire PROTAC development and it is of great interest to medicinal chemists.

PROTACs (Proteolysis-Targeting Chimeras) are considered  as a promising new approach for targeting previously 'undruggable' proteins, with growing interest in their clinical and preclinical applications across various disease indications. During the preclinical stages, what strategies or approaches can be employed to enhance the selectivity and specificity of PROTACs to minimize off-target protein degradation while maintaining efficacy? You may input from your own experiences. Thank you.