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 target/process)

4. tolerable (lower toxicity)

 

Observation on developing PROTAC - a big surprise

1. solubilize well

2. slip into cells

3. orally available

4. resist metabolic processes

5. cross blood brain-barrier (in some cases)

 

Not bringing close enough and the target will be degraded;

the degradation must be activated, requires much understanding in

the whole process.

 

Adding ubiquitin will cause the degradation through proteasomal system -- requires more insights

 

E3 ligase -- which one to be chosen and avoid the side effective

~600 human E3 ligase

1. abundance E3 ligase can be found in all tissue -- easy to degrade the target but should not cause

any problem

2. specifically express in some tissue/cancer type

3. Subcellular distribution (can be another layer of selectivity)

 

~5-6 E3 ligases validated for use in targeted degrader

 

Good point of the degrader;

no requiring the catalytic sites or well-defined pocket to bind and interfering

the function (called druggable)

Drawback;

if no ligand on the targeted -- can't design the degrader to bind and glue

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My question;

1. how do they design the molecule? - secret

2. how do they introduce the molecule and specifically kill the cancer? – good cell penetrant