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

Buckley, Dennis L.; Raina, Kanak; Darricarrère, Nicole; Hines, John; Gustafson, Jeffrey L.; Smith, Ian; Miah, Afjal H.; Harling, John D.; Crews, Craig M.

doi:10.1021/acschembio.5b00442

Cited by 327 publications

(337 citation statements)

References 39 publications

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“…Therefore, it is important to test a variety of warheads (if applicable), linkers and E3s when optimizing a specific PROTAC. In particular, the linker connecting the two functional moieties has a significant influence on PROTAC activity (Cyrus et al, 2011; Buckley et al, 2015). Its composition impacts cell permeability and an optimized linker length is essential for efficient target ubiquitination.…”

Section: Resultsmentioning

confidence: 99%

“…The R- hydroxyproline core of VHL ligand 1 is essential for VHL engagement and inversion of this stereo center abolishes binding completely. The potency of VHL ligand 1 as an efficient VHL recruiting element for PROTACs was proven by the degradation of HaloTag-GFP fusion proteins (Buckley et al, 2015). Cell treatment with various VHL ligand 1 -based haloPROTACs resulted in dose-dependent GFP depletion with a half maximal degradation concentration (DC 50 ) of 19 nM and a maximum degradation efficacy (D max ) of 90%.…”

Section: Targeted Proteasomal Degradationmentioning

confidence: 99%

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Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Cromm

Crews

2017

Cell Chemical Biology

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297

256

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Traditional pharmaceutical drug discovery is almost exclusively focused on directly controlling protein activity to cure diseases. Modulators of protein activity, especially inhibitors, are developed and applied at high concentration to achieve maximal effects. Thereby, reduced bioavailability and off-target effects can hamper compound efficacy. Nucleic acid-based strategies that control protein function by affecting expression have emerged as an alternative. However, metabolic stability and broad bioavailability represent development hurdles that remain to be overcome for these approaches. More recently, utilizing the cell’s own protein destruction machinery for selective degradation of essential drivers of human disorders has opened up a new and exciting area of drug discovery. Small molecule-induced proteolysis of selected substrates offers the potential of reaching beyond the limitations of the current pharmaceutical paradigm to expand the druggable target space.

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Section: Resultsmentioning

confidence: 99%

Section: Targeted Proteasomal Degradationmentioning

confidence: 99%

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Cromm

Crews

2017

Cell Chemical Biology

Self Cite

297

256

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“…These compounds are similar to the VHL-based PROTACs presented above: The heterobifunctional molecule binds to the E3 Ligase VHL, while the chloroalkane simultaneously forms a covalent bond with the HaloTag receptor protein (91). From a panel of different compounds, we found that HaloPROTAC3 was the most efficacious.…”

Section: Fusion-based Degron Technologiesmentioning

confidence: 97%

Targeted Protein Degradation by Small Molecules

Bondeson

Crews²

2017

Annu. Rev. Pharmacol. Toxicol.

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141

139

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Protein homeostasis networks are highly regulated systems responsible for maintaining the health and productivity of cells. Whereas therapeutics have been developed to disrupt protein homeostasis, more recently identified techniques have been used to repurpose homeostatic networks to effect degradation of disease-relevant proteins. Here, we review recent advances in the use of small molecules to degrade proteins in a selective manner. First, we highlight all-small-molecule techniques with direct clinical application. Second, we describe techniques that may find broader acceptance in the biomedical research community that require little or no synthetic chemistry. In addition to serving as innovative research tools, these new approaches to control intracellular protein levels offer the potential to develop novel therapeutics targeting proteins that are not currently pharmaceutically vulnerable.

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“…We and others have recently developed small-molecule degraders of BET proteins (23)(24)(25). These heterobifunctional molecules, known as "proteolysis targeting chimeras" (PROTACs), contain a ligand for a target protein of interest connected via a linker to a ligand for an E3 ubiquitin ligase (26,27). Thereby, treatment of cells with a PROTAC results in the formation of a trimeric complex that allows ubiquitination and subsequent degradation of the target protein via the proteasome (Fig.…”

mentioning

confidence: 99%

PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

Raina

Lü

Qian

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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639

627

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Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extraterminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.BET | BRD4 | protein degradation | prostate | PROTAC

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

Cited by 327 publications

References 39 publications

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Targeted Protein Degradation by Small Molecules

PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

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