Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool

Lee, Hyosung; Puppala, Dinesh; Choi, Eunyoung; Swanson, Hollie I.; Kim, Kyung‐Bo

doi:10.1002/cbic.200700438

Cited by 78 publications

(54 citation statements)

References 79 publications

(53 reference statements)

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“…Apigenin-Protac and Apigenin-Protac[Ala] were synthesized as described previously (Lee et al, 2007). TCDD was a generous gift from Dr. Stephen H. Safe (Texas A&M University, College Station, TX).…”

Section: Methodsmentioning

confidence: 99%

“…The apigenin-based AHR-targeting PROTACS (ApigeninProtac) was synthesized as described previously (Lee et al, 2007) (Fig. 1B).…”

Section: Apigenin-protac Specifically Interacts With the Ahrmentioning

confidence: 99%

“…For the majority of our experiments, we have . Apigenin-Protac and Apigenin-Protac[Ala] were synthesized as described previously (Lee et al, 2007). To generate the negative control of Apigenin-Protac, hydroxy proline, the key amino acid in the pentapeptide pVHL E3 ubiquitin ligase recognition site (Hon et al, 2002) was replaced by alanine, resulting in Apigenin-Protac [Ala].…”

Section: Apigenin-protac Specifically Interacts With the Ahrmentioning

confidence: 99%

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Development of an Aryl Hydrocarbon Receptor Antagonist Using the Proteolysis-Targeting Chimeric Molecules Approach: A Potential Tool for Chemoprevention

Puppala

Lee²,

Kim³

et al. 2008

Mol Pharmacol

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Activation of the aryl hydrocarbon receptor (AHR) by agonists and environmental contaminants like dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) leads to many adverse biological effects, including tumor promotion. With this in mind, we propose that agents that block the AHR pathway may be therapeutically beneficial, particularly by exhibiting chemopreventive activities. In our current research, we have focused on the development of an AHR antagonist using a chemical genetic approach called PROTACS (PROteolysis-TArgeting Chimeric moleculeS). PROTACS is a novel approach of tagging small recognition sequences of a specific E3 ubiquitin ligase complex to a known ligand for the receptor of interest (AHR) for targeting its degradation. Here, we present the design and initial characterization of AHR targeting PROTACS (ApigeninProtac) designed to degrade and inhibit the AHR in epithelial cells. Our results demonstrate the "proof of concept" of this approach in effectively blocking AHR activity in cultured cells.Exposures to environmental factors are believed to play a substantial role in the development of many human cancers

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Section: Methodsmentioning

confidence: 99%

“…The apigenin-based AHR-targeting PROTACS (ApigeninProtac) was synthesized as described previously (Lee et al, 2007) (Fig. 1B).…”

Section: Apigenin-protac Specifically Interacts With the Ahrmentioning

confidence: 99%

Section: Apigenin-protac Specifically Interacts With the Ahrmentioning

confidence: 99%

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Development of an Aryl Hydrocarbon Receptor Antagonist Using the Proteolysis-Targeting Chimeric Molecules Approach: A Potential Tool for Chemoprevention

Puppala

Lee²,

Kim³

et al. 2008

Mol Pharmacol

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“…5, 7, 9, 11 We recently described the synthesis of potent ligands for VHL based upon a key hydroxyproline residue. Crystallographic evidence indicated that these ligands contained numerous sites that were solvent exposed, suggesting possible linker positions.…”

Section: Introductionmentioning

confidence: 99%

HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins

Buckley¹,

Raina²,

et al. 2015

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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 knockdown widely used HaloTag7 fusion proteins in a general fashion.

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“…In addition, a dihydroxytestosterone-HIF-Arg 8 construct was shown to degrade the AR in HEK293 cells expressing AR-GFP. Cell-permeable PROTACs consisting of fumagillin, apigenin, and estrogen derivatives conjugated via a linker to the HIF1␣ peptide sequence, designed to target MetAP-2, the aryl hydrocarbon receptor, and the ER, respectively, have subsequently been reported by Kim and co-workers (24,25). To address the cell permeability issue associated with the high molecular weight of earlier PROTACs, our group reported the first all-small molecule PROTAC targeting the AR in HeLa cells (26).…”

Section: Protacsmentioning

confidence: 99%

Chemical Inducers of Targeted Protein Degradation

Raina

Crews

2010

Journal of Biological Chemistry

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Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool

Cited by 78 publications

References 79 publications

Development of an Aryl Hydrocarbon Receptor Antagonist Using the Proteolysis-Targeting Chimeric Molecules Approach: A Potential Tool for Chemoprevention

Development of an Aryl Hydrocarbon Receptor Antagonist Using the Proteolysis-Targeting Chimeric Molecules Approach: A Potential Tool for Chemoprevention

HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins

Chemical Inducers of Targeted Protein Degradation

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