SMASh (Small-Molecule-Assisted Shutoff) degron system was developed and optimized to allow targeted and time-controlled degradation of a protein of interest. It was built as a self-cleaving degron that can be stabilized upon drug treatment (Chung HK et al. Nat Chem Biol 2015).
This drug-inducible and reversible protein degradation system is of particular interest to model-targeted protein degradation therapeutic approaches in preclinical stages (learn more: Targeted Protein Degradation: New Promises for "Undruggable" Diseases). It can also be used to create targeted inducible and reversible knock-out and knock-down systems.
SMASh does not need to be coupled to any other reagent to function; a single genetic modification allows for the development of an inducible and reversible targeted protein degradation system.
The SMASh degron system was developed and first described in 2015 (Chung HK et al. Nat Chem Biol 2015 and US62/186,339). It has been shown to be functional in yeast, virus, and mammalian cells, and has been used in drug discovery (Rago et al. Biochem Biophys Res Commun 2019).
Without the drug, the SMASh tag self-cleaved from the protein of interest and is then degraded, with an unchanged level of expression of the protein of interest.
With the drug (in green), the SMASh-tag is stabilized and so, does not self-cleave, allowing for targeted degradation of the protein of interest.
Rago F, DiMare MT, Elliott G, Ruddy DA, Sovath S, Kerr G, Bhang HC, Jagani Z. Degron mediated BRM/SMARCA2 depletion uncovers novel combination partners for treatment of BRG1/SMARCA4-mutant cancers. Biochem Biophys Res Commun. 2019 Jan 1;508(1):109–116.
Chung HK, Jacobs CL, Huo Y, Yang J, Krumm SA, Plemper RK, Tsien RY, Lin MZ. Tunable and reversible drug control of protein production via a self-excising degron. Nat Chem Biol. 2015 Sep;11(9):713–20.
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