Note for: First targeted protein degrader hits the clinic (fun to read)
Note: First targeted protein degrader hits the clinic (doi: 10.1038/d41573-019-00043-6 ) Protein degrader -- novel approach to kill cancer; Design the new molecule which can link between E3-ligase + targeted molecule --> targeted molecule undergoes proteasomal degradation (ubiquitinylation) alternative approaches besides the degrader; 1. small molecule interfering on protein stability (fold-unfold equilibrium) 2. target the upstream factors controlling protein stability/abundance 3. disrupting the protein-protein interaction and multi-target complexes 4. targeting deubiquitination process -- maintain the degradation on the particular target Targeted degrader idea -- patent 1999 Degrader structure (bifunctional small molecule): 1. target-binding warhead 2. linker 3. E3 ligase recruiter Basic drug properties; 1. bioavailable (amount in blood circulation) 2. selective 3. effective (disease relies on this ta...