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Shanshan Gu, Danrui Cui, Xiaoyu Chen, Xiufang Xiong, Yongchao Zhao
Proteolysis-targeting chimeric molecules (PROTACs) represent an emerging technique that is receiving much attention for therapeutic intervention. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The hetero-bifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate "undruggable" protein targets, such as transcription factors and non-enzymatic proteins, which are not limited to physiological substrates of the ubiquitin-proteasome system...
February 23, 2018: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
(no author information available yet)
Biotechnology startup Arvinas is developing proteolysis-targeting chimeras (PROTAC) that combat cancer by degrading disease-causing proteins. The company's first PROTACs will target prostate and breast cancers, and a recent deal with Pfizer will allow Arvinas to develop PROTACs for other cancer types.
February 16, 2018: Cancer Discovery
Kelly M DeMars, Changjun Yang, Carolina I Castro-Rivera, Eduardo Candelario-Jalil
Bromodomain and extraterminal (BET) proteins are essential to pro-inflammatory gene transcription. The BET family proteins, BRD2, BRD3, BRD4, and testis-specific BRDT, couple chromatin remodeling to gene transcription, acting as histone acetyltransferases, scaffolds for transcription complexes, and markers of histone acetylation. To initiate an inflammatory response, cells undergo de novo gene transcription requiring histone-modifying proteins to make DNA wrapped around histones more or less readily available to transcription complexes...
February 12, 2018: Biochemical and Biophysical Research Communications
Mengchen Lu, Tian Liu, Qiong Jiao, Jianai Ji, Mengmin Tao, Yijun Liu, Qidong You, Zhengyu Jiang
Induced protein degradation by PROTACs has emerged as a promising strategy to target nonenzymatic proteins inside the cell. The aim of this study was to identify Keap1, a substrate adaptor protein for ubiquitin E3 ligase involved in oxidative stress regulation, as a novel candidate for PROTACs that can be applied in the degradation of the nonenzymatic protein Tau. A peptide PROTAC by recruiting Keap1-Cul3 ubiquitin E3 ligase was developed and applied in the degradation of intracellular Tau. Peptide 1 showed strong in vitro binding with Keap1 and Tau...
February 1, 2018: European Journal of Medicinal Chemistry
Matthias P Müller, Daniel Rauh
In this issue of Cell Chemical Biology, Bondeson et al. (2018), Burslem et al. (2018), and Huang et al. (2018) systematically characterize proteolysis-targeting chimeras (PROTACs) regarding their specificity and general advantages of targeted proteolysis of cellular proteins and provide interesting insights into possible future developments.
January 18, 2018: Cell Chemical Biology
Hu Lei, Weiwei Wang, Yingli Wu
Oncoproteins play a vital role in the pathogenesis of myeloid leukemia. Most targeted therapies for myeloid leukemia are small molecules or monoclonal antibodies that inhibit the activity of the oncoproteins. However, leukemia cells often develop resistance to these drugs through overexpression of the target protein and/or by obtaining new mutations in the target protein to render them resistant to the drug. Oncoproteins degradation induced by small molecules through ubiquitin or autophagy pathway is considered a better way to avoid drug resistance...
December 4, 2017: Leukemia & Lymphoma
Ian Churcher
Targeted protein degradation, using bifunctional small molecules (Protacs) to remove specific proteins from within cells, has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing approaches. In this Perspective, the brief history of the field is surveyed from a drug discovery perspective with a focus on the key advances in knowledge which have led to the definition and exemplification of protein degradation concepts and their resulting applications to medicine discovery...
January 25, 2018: Journal of Medicinal Chemistry
Daniel P Bondeson, Blake E Smith, George M Burslem, Alexandru D Buhimschi, John Hines, Saul Jaime-Figueroa, Jing Wang, Brian D Hamman, Alexey Ishchenko, Craig M Crews
Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases...
November 9, 2017: Cell Chemical Biology
George M Burslem, Blake E Smith, Ashton C Lai, Saul Jaime-Figueroa, Daniel C McQuaid, Daniel P Bondeson, Momar Toure, Hanqing Dong, Yimin Qian, Jing Wang, Andrew P Crew, John Hines, Craig M Crews
Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target-degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors...
October 25, 2017: Cell Chemical Biology
Scott J Hughes, Alessio Ciulli
Molecular glues and bivalent inducers of protein degradation (also known as PROTACs) represent a fascinating new modality in pharmacotherapeutics: the potential to knockdown previously thought 'undruggable' targets at sub-stoichiometric concentrations in ways not possible using conventional inhibitors. Mounting evidence suggests these chemical agents, in concert with their target proteins, can be modelled as three-body binding equilibria that can exhibit significant cooperativity as a result of specific ligand-induced molecular recognition...
November 8, 2017: Essays in Biochemistry
James J Driscoll, Magen Brailey
Multiple myeloma (MM) is a clonal plasma cell malignancy which, despite recent treatment advances, remains incurable in the vast majority of the over 118,000 patients in the USA afflicted with this disease. Treatment of MM has dramatically improved in the past decade with the introduction of new drugs into therapeutic strategies in both the frontline and relapse settings that has led to a significant improvement in the median overall survival (OS). These drugs have been incorporated into clinical guidelines and transformed the treatment approach to MM...
December 2017: Cancer Metastasis Reviews
Chiara Maniaci, Scott J Hughes, Andrea Testa, Wenzhang Chen, Douglas J Lamont, Sonia Rocha, Dario R Alessi, Roberto Romeo, Alessio Ciulli
E3 ubiquitin ligases are key enzymes within the ubiquitin proteasome system which catalyze the ubiquitination of proteins, targeting them for proteasomal degradation. E3 ligases are gaining importance as targets to small molecules, both for direct inhibition and to be hijacked to induce the degradation of non-native neo-substrates using bivalent compounds known as PROTACs (for 'proteolysis-targeting chimeras'). We describe Homo-PROTACs as an approach to dimerize an E3 ligase to trigger its suicide-type chemical knockdown inside cells...
October 10, 2017: Nature Communications
Honorine Lebraud, Tom D Heightman
In a time of unprecedented challenges in developing potent, selective and well-tolerated protein inhibitors as therapeutics, drug hunters are increasingly seeking alternative modalities to modulate pharmacological targets. Selective inhibitors are achievable for only a fraction of the proteome, and are not guaranteed to elicit the desired response in patients, especially when pursuing targets identified through genetic knockdown. Targeted protein degradation holds the potential to expand the range of proteins that can be effectively modulated...
October 2, 2017: Essays in Biochemistry
Christopher D McCune, Matthew L Beio, Jill M Sturdivant, Roberto de la Salud-Bea, Brendan M Darnell, David B Berkowitz
Developing specific chemical functionalities to deploy in biological environments for targeted enzyme inactivation lies at the heart of mechanism-based inhibitor development but also is central to other protein-tagging methods in modern chemical biology including activity-based protein profiling and proteolysis-targeting chimeras. We describe here a previously unknown class of potential PLP enzyme inactivators; namely, a family of quaternary, α-(1'-fluoro)vinyl amino acids, bearing the side chains of the cognate amino acids...
October 11, 2017: Journal of the American Chemical Society
Pedro Soares, Morgan S Gadd, Julianty Frost, Carles Galdeano, Lucy C J Ellis, Ola Epemolu, Sonia Rocha, Kevin D Read, Alessio Ciulli
The von Hippel-Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins...
August 30, 2017: Journal of Medicinal Chemistry
Joseph T Madak, Christine R Cuthbertson, Wenmin Chen, Hollis D Showalter, Nouri Neamati
Brequinar, a potent dihydroorotate dehydrogenase (DHODH) inhibitor, has been evaluated in multiple clinical trials as a potential treatment for cancer. To further understand brequinar-based DHODH inhibition and DHODH's therapeutic relevance in cancer, we have developed novel brequinar-based probes. We disclose a 16-step convergent synthesis of the first brequinar-PROTAC and a four-step approach towards the first mitochondrial-directed brequinar probe. A PROTAC and mitochondria-directed probe of brequinar both possess cytotoxicity that is superior to brequinar in a colony formation assay...
August 21, 2017: Chemistry: a European Journal
Philipp Ottis, Momar Toure, Philipp M Cromm, Eunhwa Ko, Jeffrey L Gustafson, Craig M Crews
Proteolysis targeting chimera (PROTAC) technology, the recruitment of E3 ubiquitin ligases to induce the degradation of a protein target, is rapidly impacting chemical biology, as well as modern drug development. Here, we explore the universality of this approach by evaluating different E3 ubiquitin ligases, engineered in their substrate binding domains to accept a recruiting ligand. Five out of six E3 ligases were found to be amenable to recruitment for target degradation. Taking advantage of the tight spatiotemporal control of inducing ubiquitination on a preselected target in living cells, we focused on two of the engineered E3 ligases, βTRCP and parkin, to unravel their ubiquitination characteristics in comparison with the PROTAC-recruited endogenous E3 ligases VHL and cereblon...
October 20, 2017: ACS Chemical Biology
Andrew P Crew, Kanak Raina, Hanqing Dong, Yimin Qian, Jing Wang, Dominico Vigil, Yevgeniy V Serebrenik, Brian D Hamman, Alicia Morgan, Caterina Ferraro, Kam Siu, Taavi K Neklesa, James D Winkler, Kevin G Coleman, Craig M Crews
Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that recruit an E3 ligase to a target protein to facilitate ubiquitination and subsequent degradation of that protein. While the field of targeted degraders is still relatively young, the potential for this modality to become a differentiated and therapeutic reality is strong, such that both academic and pharmaceutical institutions are now entering this interesting area of research. In this article, we describe a broadly applicable process for identifying degrader hits based on the serine/threonine kinase TANK-binding kinase 1 (TBK1) and have generalized the key structural elements associated with degradation activities...
July 10, 2017: Journal of Medicinal Chemistry
B Sun, W Fiskus, Y Qian, K Rajapakshe, K Raina, K G Coleman, A P Crew, A Shen, D T Saenz, C P Mill, A J Nowak, N Jain, L Zhang, M Wang, J D Khoury, C Coarfa, C M Crews, K N Bhalla
Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and NFkB target genes, which undermines the growth and survival of MCL cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells...
June 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Caroline M Robb, Jacob I Contreras, Smit Kour, Margaret A Taylor, Mohammad Abid, Yogesh A Sonawane, Muhammad Zahid, Daryl J Murry, Amarnath Natarajan, Sandeep Rana
Cyclin-dependent kinase 9 (CDK9), a member of the cyclin-dependent protein kinase (CDK) family, is involved in transcriptional elongation of several target genes. CDK9 is ubiquitously expressed and has been shown to contribute to a variety of malignancies such as pancreatic, prostate and breast cancers. Here we report the development of a heterobifunctional small molecule proteolysis targeting chimera (PROTAC) capable of cereblon (CRBN) mediated proteasomal degradation of CDK9. In HCT116 cells, it selectively degrades CDK9 while sparing other CDK family members...
July 4, 2017: Chemical Communications: Chem Comm
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