title: HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins.
abstract: Small molecule-induced protein degradation is an attractive strategy for the development of chemical probes. One method for inducing targeted protein degradation involves the use of PROTACs, heterobifunctional molecules that can recruit specific E3 ligases to a desired protein of interest. PROTACs have been successfully used to degrade numerous proteins in cells, but the peptidic E3 ligase ligands used in previous PROTACs have hindered their development into more mature chemical probes or therapeutics. We report the design of a novel class of PROTACs that incorporate small molecule VHL ligands to successfully degrade HaloTag7 fusion proteins. These HaloPROTACs will inspire the development of future PROTACs with more drug-like properties. Additionally, these HaloPROTACs are useful chemical genetic tools, due to their ability to chemically knock down widely used HaloTag7 fusion proteins in a general fashion.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Buckley
authors.forename: Kanak
authors.initials: K
authors.lastname: Raina
authors.forename: Nicole
authors.initials: N
authors.lastname: Darricarrere
authors.forename: John
authors.initials: J
authors.lastname: Hines
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Gustafson
authors.affiliation: ∥Protein Degradation Discovery Performance Unit, GlaxoSmithKline, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Smith
authors.affiliation: ∥Protein Degradation Discovery Performance Unit, GlaxoSmithKline, Stevenage, SG1 2NY, United Kingdom.
authors.forename: Afjal H
authors.initials: AH
authors.lastname: Miah
authors.affiliation: ∥Protein Degradation Discovery Performance Unit, GlaxoSmithKline, Stevenage, SG1 2NY, United Kingdom.
authors.forename: John D
authors.initials: JD
authors.lastname: Harling
authors.forename: Craig M
authors.initials: CM
authors.lastname: Crews
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D059748:Proteolysis; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D008024:Ligands; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries; D044767:Ubiquitin-Protein Ligases