Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction

Buckley, Dennis L.; Molle, Inge Van; Gareiss, Peter C.; Tae, Hyun Seop; Michel, Julien; Noblin, Devin J.; Jorgensen, William L.; Ciulli, Alessio; Crews, Craig M.

doi:10.1021/ja209924v

Cited by 441 publications

(400 citation statements)

References 29 publications

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“…E3 ubiquitin ligases, which bind protein targets and lead to their ubiquitination and subsequent degradation, are attractive drug targets due to their exquisite substrate specificity (35). The VHL complex is an E3 ubiquitin ligase with therapeutic potential.…”

Section: Resultsmentioning

confidence: 99%

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Ligand deconstruction: Why some fragment binding positions are conserved and others are not

Kozakov

Hall

Jehle

et al. 2015

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

102

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Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots—regions of the protein where interactions with a ligand contribute substantial binding free energy—the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand.

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Section: Resultsmentioning

confidence: 99%

“…The VHL complex is an E3 ubiquitin ligase with therapeutic potential. The primary substrate of VHL is HIF-1α, a transcription factor that up-regulates numerous genes (35). Van Molle et al described the deconstruction of inhibitor 6 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Ligand deconstruction: Why some fragment binding positions are conserved and others are not

Kozakov

Hall

Jehle

et al. 2015

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

102

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“…To meet our twin goals of developing a highly potent BET protein degrader that also possesses a pharmacokinetic (PK) profile favorable for in vivo testing, we used the triazolo-diazepine acetamide BET-binding moiety derived from BET inhibitors in clinical development (29). The BET-binding ligand was conjugated via a connecting linker to a recently described HIF-1α-derived (R)-hydroxyproline containing a VHL E3 ligase-binding ligand (30) to generate BET PROTACs. Lead molecules generated by varying linker length and composition were optimized for drug-like properties to obtain PROTACs suitable for in vivo studies.…”

Section: Significancementioning

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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686

654

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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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“…Another small molecule was recently designed to interfere with the binding between the transcriptional activator HIF and the vHL E3 ligase protein (43). This may be an attractive therapeutic strategy for anemia and ischemia, although additional studies are needed to determine the side effect profile before further drug development can proceed.…”

Section: Therapeuticsmentioning

confidence: 99%

Emerging therapies targeting the ubiquitin proteasome system in cancer

Weathington¹,

Mallampalli²

2014

J. Clin. Invest.

112

104

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The ubiquitin proteasome system (UPS) is an essential metabolic constituent of cellular physiology that tightly regulates cellular protein concentrations with specificity and precision to optimize cellular function. Inhibition of the proteasome has proven very effective in the treatment of multiple myeloma, and this approach is being tested for utility in other malignancies. New pharmaceuticals targeting the proteasome itself or specific proximal pathways of the UPS are in development as antiproliferatives or immunomodulatory agents. In this article, we discuss the biology of UPS-targeting drugs, their use as therapy for neoplasia, and the state of clinical and preclinical development for emerging therapeutics. IntroductionA new era in myeloma therapy. At the turn of the millennium, targeted molecular therapeutics against hematologic malignancies initiated a shift in our perspective on treatment, prognosis, and survival for patients with some of the most aggressive and fatal neoplasms. Bortezomib (branded and marketed as Velcade by Millennium Pharmaceuticals) entered the armamentarium of new antiproliferative therapies with approval in May 2003 for the hematologic malignancy multiple myeloma (MM), in which B cellderived plasma cells clonally proliferate and produce large quantities of monoclonal antibody. MM can be a devastating disease, with renal failure, blood hyperviscosity, and bone marrow invasion seen clinically. Before 2000, there were few life-prolonging therapies for the disease. Bortezomib blocks the proteolytic activity of the 26S proteasome, a cellular structure whose role in cell metabolism has now been meticulously characterized; indeed, bortezomib is the first agent available for use in humans that inhibits the activity of this system. Bortezomib quickly proved effective in refractory MM (1), and its inclusion in initial MM treatment was superior to the conventional cytotoxic chemotherapy regimen alone (2).During this time thalidomide, an agent that produced deformities in infants of mothers prescribed the drug during pregnancy, further suppressed myeloma plasma cell proliferation when added to the regimen. A decade of careful clinical trials since these first breakthrough observations has revealed that therapeutic combinations including bortezomib with thalidomide or related compounds (collectively called immunomodulatory drugs, or IMiDs) and steroids confer a very favorable prognosis compared with historic therapy, greatly prolonging the median survival time from diagnosis over this period (3). When this therapy is implemented in conjunction with autologous bone marrow stem cell transplant, recent clinical trials show a three-year progression-free survival of 60% and overall survival of 90% for patients eligible for stem cell transplant (4), compared with only 48% three-year relative survival for patients diagnosed in 1999 (5). Multiple clinical trials for this new generation of MM molecular therapies are underway, with median survival projected by some to exceed 10 years in the post-bortezomib...

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Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction

Cited by 441 publications

References 29 publications

Ligand deconstruction: Why some fragment binding positions are conserved and others are not

Ligand deconstruction: Why some fragment binding positions are conserved and others are not

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

Emerging therapies targeting the ubiquitin proteasome system in cancer

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