Catalytic in vivo protein knockdown by small-molecule PROTACs

Bondeson, Daniel P.; Mares, Alina; Smith, Ian; Ko, Eunhwa; Campos, Sébastien; Miah, Afjal H.; Mulholland, Katie E; Routly, Natasha; Buckley, Dennis L.; Gustafson, Jeffrey L.; Zinn, Nico; Grandi, Paola; Shimamura, Satoko; Bergamini, Giovanna; Faelth-Savitski, Maria; Bantscheff, Marcus; Cox, Carly; Gordon, Deborah; Willard, Ryan R.; Flanagan, John J.; Casillas, Linda; Votta, Bartholomew J.; Besten, Willem den; Famm, Kristoffer; Kruidenier, Laurens; Carter, Paul S.; Harling, John D.; Churcher, Ian; Crews, Craig M.

doi:10.1038/nchembio.1858

Cited by 956 publications

(1,109 citation statements)

References 52 publications

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“…S2A). However, ARV-766 demonstrated only marginal suppression of c-MYC, suggesting that BET PROTACs have lower cellular permeability than JQ-1 and that the remarkable potency of ARV-771 is most likely caused by the "catalytic" nature of its cellular activity (26). The c-MYC suppression was indeed at the mRNA level, as determined by quantitative PCR (qPCR) (Fig.…”

Section: Significancementioning

confidence: 97%

“…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.…”

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confidence: 99%

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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.

667

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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Section: Significancementioning

confidence: 97%

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.

667

654

View full text Add to dashboard Cite

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“…Recruitment of this target protein to the E3 ubiquitin ligase facilitates ubiquitination and subsequent degradation of the target protein 22 . This principle has been successfully applied to several targets including the Bromodomain and Extra Terminal (BET) family (BRD2, BRD3, BRD4), RIPK2, BCR-ABL, FKBP12, BRD9, and ERRα 2,4,6,23–26 and represents a promising new pharmacologic modality now widely explored in chemical biology and drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Plasticity in binding confers selectivity in ligand-induced protein degradation

et al. 2018

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SUMMARY Heterobifunctional small molecule degraders that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. However, we currently lack a detailed understanding of the molecular basis for target recruitment and selectivity, which is critically required to enable rational design of degraders. Here we utilize comprehensive characterization of the ligand dependent CRBN/BRD4 interaction to demonstrate that binding between proteins that have not evolved to interact is plastic. Multiple X-ray crystal structures show that plasticity results in several distinct low energy binding conformations, which are selectively bound by ligands. We demonstrate that computational protein-protein docking can reveal the underlying inter-protein contacts and inform the design of a BRD4 selective degrader that can discriminate between highly homologous BET bromodomains. Our findings that plastic inter-protein contacts confer selectivity for ligand-induced protein dimerization provide a conceptual framework for the development of heterobifunctional ligands.

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“…On the other hand, in some cases the entire KMTase protein may need to be eliminated to achieve anticancer activity. To overcome this challenge, one could use small molecule ligands capable of targeting proteins for proteolytic degradation [149,150]. For example, Winter et al have recently found that coupling a ligand of a target protein to thalidomide results in engagement of the cellular ubiquitin ligase machinery and degradation of the target protein [149].…”

Section: Alternative Druggable Regions Of H3k36 Kmtase Proteinsmentioning

confidence: 99%

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

2016

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Methylation at histone 3, lysine 36 (H3K36) is a conserved epigenetic mark regulating gene transcription, alternative splicing and DNA repair. Genes encoding H3K36 methyltransferases (KMTases) are commonly overexpressed, mutated or involved in chromosomal translocations in cancer. Molecular biology studies have demonstrated that H3K36 KMTases regulate oncogenic transcriptional programs. Structural studies of the catalytic SET domain of H3K36 KMTases have revealed intriguing opportunities for design of small molecule inhibitors. Nevertheless, potent inhibitors for most H3K36 KMTases have not yet been developed, underlining the challenges associated with this target class. As we now have strong evidence linking H3K36 KMTases to cancer, drug development efforts are predicted to yield novel compounds in the near future. Cellular development and differentiation are controlled by post-translational modifications on DNA and histone proteins, forming an epigenetic (above the genes) regulatory network. Disruption of epigenetic pathways is a nearly universal feature of cancer, causing aberrations in gene expression and genome integrity (reviewed in [1]). A key group of epigenetic enzymes disrupted in cancer is the lysine methyltransferases (KMTases), which install methyl groups on histone proteins. In cancer cells, methylation performed by KMTases drives proliferation and halts differentiation by modifying gene transcription and other DNA-templated processes [2][3][4]. Over the past decade, KMTases have emerged as important drug targets for both industrial and academic research groups. Some progress has been made, most notably by selective inhibitors for the EZH2 and DOT1L KMTases that have reached clinical trials for the treatment of nonHodgkin lymphoma and acute leukemia, respectively [5,6]. Nevertheless, selective and cell permeable inhibitors for many KMTases remain unavailable.Methylation at H3K36 represents a particularly important chromatin mark implicated in diverse forms of cancer. KMTases with specificity toward H3K36 are overexpressed in cancer cells and have been characterized as regulators of cell growth, differentiation, stemness and DNA repair pathways [7][8][9]. However, very few selective and cell-active small molecule inhibitors of H3K36-specfic KMTases have been reported to date. In this article, we provide an overview of cellular pathways involving H3K36 methylation and discuss the diverse functions carried out by the eight different human H3K36-specific KMTases. Then we analyze structural characteristics of the catalytic SET domain of H3K36 KMTases and evaluate prospects for their inhibition by small molecules. Review Rogawski, Grembecka & Cierpicki We conclude with a discussion of the challenges and o pportunities for targeting these proteins. SPECIAL FOCUS y Epigenetic drug discovery H3K36 methylation regulates diverse processes implicated in cancerH3K36 methylation participates in a wide variety of nuclear pathways. Many of these processes, including transcriptional regulation, alternative spli...

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Catalytic in vivo protein knockdown by small-molecule PROTACs

Cited by 956 publications

References 52 publications

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

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

Plasticity in binding confers selectivity in ligand-induced protein degradation

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

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