PROTACs: Current Trends in Protein Degradation by Proteolysis-Targeting Chimeras

VHL-Modified PROteolysis TArgeting Chimeras (PROTACs) as a Strategy to Evade Metabolic Degradation in In Vitro Applications

“…These events might be explained by the structural diversity between compounds 1 and 2 : the first is a PROTAC with MW corresponding to 882 Da, whereas the second one is a small molecule. ,, Hence, the two molecules lend themselves to the formation of different chemical interactions, presumably leading to the binding of two PEP isoforms. Additional genomic investigations might serve to prove our hypothesis.…”

“…General procedure A (3 h) was followed by using 28 (0.220 g, 0.394 mmol) and 4.0 N HCl in dioxane (2.0 mL) to afford the titled compound as a white solid (0.192 g, 98% yield). 1 (7). General procedure B (3 h) was followed by using 14 (0.030 g, 0.066 mmol) and 5 (0.031 g, 0.066 mmol) to afford the titled compound as a clear yellow solid (0.015 g, 26% yield) after purification by automated flash chromatography on a SiO 2 cartridge (DCM/MeOH/Acetone, 87:3:10).…”

“…PROTACs are heterobifunctional molecules triggering proteasome-mediated protein degradation once in the cell cytosol. − Such an unconventional mode of action has attracted attention to tackle human diseases ,, and to overcome the drawbacks associated with traditional therapeutics ( e.g ., siRNAs, antibodies, and small molecules) . The originality of PROTACs depends on the theoretical coexistence in one single molecule of the cornerstones of ordinary therapeutic approaches, including (1) the potential to modulate protein expression as RNA-based drugs may accomplish and (2) the cell permeability that remains the prerogative of small molecules.…”

“…Despite the great success achieved so far in identifying potent degraders for a wide set of disease-related target proteins with good efficacy in vitro and in vivo , the pharmacokinetics of PROTACs has remained challenging. ,− For instance, their oral bioavailability is still limited, ,, and consequently, various cheminformatics approaches have been developed to scrutinize orally bioavailable PROTACs and to provide tools for the development of compounds with an ameliorated oral absorption. , …”

Computational strategies for PROTAC drug discovery

“…Through specific binding to the target proteins, the PROTAC recruits an E3 ligase and causes the ubiquitination and subsequent degradation of the target proteins via the UPS [3][4][5]. This technology has two advantages: the PROTACbinding sites on the same target protein may be infinite [6], and binding and degradation activities may occur in multiple target proteins, thus enabling smaller drug dosages and pharmacological effect observations [7][8][9].…”