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https://www.readbyqxmd.com/read/29144739/protac-induced-protein-degradation-in-drug-discovery-breaking-the-rules-or-just-making-new-ones
#1
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...
November 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29129718/lessons-in-protac-design-from-selective-degradation-with-a-promiscuous-warhead
#2
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...
October 31, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29129716/the-advantages-of-targeted-protein-degradation-over-inhibition-an-rtk-case-study
#3
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
https://www.readbyqxmd.com/read/29118097/molecular-recognition-of-ternary-complexes-a-new-dimension-in-the-structure-guided-design-of-chemical-degraders
#4
REVIEW
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
https://www.readbyqxmd.com/read/29052093/emerging-small-molecule-approaches-to-enhance-the-antimyeloma-benefit-of-proteasome-inhibitors
#5
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...
October 19, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29018234/homo-protacs-bivalent-small-molecule-dimerizers-of-the-vhl-e3-ubiquitin-ligase-to-induce-self-degradation
#6
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
https://www.readbyqxmd.com/read/28970340/protein-degradation-a-validated-therapeutic-strategy-with-exciting-prospects
#7
REVIEW
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
https://www.readbyqxmd.com/read/28906111/synthesis-and-deployment-of-an-elusive-fluorovinyl-cation-equivalent-access-to-quaternary-%C3%AE-1-fluoro-vinyl-amino-acids-as-potential-plp-enzyme-inactivators
#8
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
https://www.readbyqxmd.com/read/28853884/group-based-optimization-of-potent-and-cell-active-inhibitors-of-the-von-hippel-lindau-vhl-e3-ubiquitin-ligase-structure-activity-relationships-leading-to-the-chemical-probe-2s-4r-1-s-2-1-cyanocyclopropanecarboxamido-3-3-dimethylbutanoyl-4-hydroxy-n-4-4-methylthiazol
#9
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
https://www.readbyqxmd.com/read/28833638/design-synthesis-and-characterization-of-brequinar-conjugates-as-probes-to-study-dhodh-inhibition
#10
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
https://www.readbyqxmd.com/read/28767222/assessing-different-e3-ligases-for-small-molecule-induced-protein-ubiquitination-and-degradation
#11
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...
September 5, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28692295/identification-and-characterization-of-von-hippel-lindau-recruiting-proteolysis-targeting-chimeras-protacs-of-tank-binding-kinase-1
#12
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
https://www.readbyqxmd.com/read/28663582/bet-protein-proteolysis-targeting-chimera-protac-exerts-potent-lethal-activity-against-mantle-cell-lymphoma-cells
#13
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
https://www.readbyqxmd.com/read/28636052/chemically-induced-degradation-of-cdk9-by-a-proteolysis-targeting-chimera-protac
#14
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
https://www.readbyqxmd.com/read/28605671/targeted-protein-knockdown-using-small-molecule-degraders
#15
REVIEW
Kanak Raina, Craig M Crews
Small molecule probes of biological systems have traditionally been designed to bind to and inhibit the active sites of their protein targets. While this class of pharmacological agents has been broadened by the development of a small number of allosteric and protein-protein interaction (PPI) inhibitors, conventional drug design still excludes 'undruggable' proteins that are neither enzymes nor receptors. Recent years have seen the emergence of new classes of small molecules that can target hitherto undruggable proteins by recruiting the cellular proteostasis machinery to selectively tag them for degradation...
August 2017: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/28595007/impact-of-target-warhead-and-linkage-vector-on-inducing-protein-degradation-comparison-of-bromodomain-and-extra-terminal-bet-degraders-derived-from-triazolodiazepine-jq1-and-tetrahydroquinoline-i-bet726-bet-inhibitor-scaffolds
#16
Kwok-Ho Chan, Michael Zengerle, Andrea Testa, Alessio Ciulli
The design of proteolysis-targeting chimeras (PROTACs) is a powerful small-molecule approach for inducing protein degradation. PROTACs conjugate a target warhead to an E3 ubiquitin ligase ligand via a linker. Here we examined the impact of derivatizing two different BET bromodomain inhibitors, triazolodiazepine JQ1 and the more potent tetrahydroquinoline I-BET726, via distinct exit vectors, using different polyethylene glycol linkers to VHL ligand VH032. Triazolodiazepine PROTACs exhibited positive cooperativities of ternary complex formation and were more potent degraders than tetrahydroquinoline compounds, which showed negative cooperativities instead...
June 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28587164/chemical-methods-to-knock-down-the-amyloid-proteins
#17
REVIEW
Na Gao, Yong-Xiang Chen, Yu-Fen Zhao, Yan-Mei Li
Amyloid proteins are closely related with amyloid diseases and do tremendous harm to human health. However, there is still a lack of effective strategies to treat these amyloid diseases, so it is important to develop novel methods. Accelerating the clearance of amyloid proteins is a favorable method for amyloid disease treatment. Recently, chemical methods for protein reduction have been developed and have attracted much attention. In this review, we focus on the latest progress of chemical methods that knock down amyloid proteins, including the proteolysis-targeting chimera (PROTAC) strategy, the "recognition-cleavage" strategy, the chaperone-mediated autophagy (CMA) strategy, the selectively light-activatable organic and inorganic molecules strategy and other chemical strategies...
June 1, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28552582/proteasome-activation-by-small-molecules
#18
Yves Leestemaker, Annemieke de Jong, Katharina F Witting, Renske Penning, Karianne Schuurman, Boris Rodenko, Esther A Zaal, Bert van de Kooij, Stefan Laufer, Albert J R Heck, Jannie Borst, Wiep Scheper, Celia R Berkers, Huib Ovaa
Drugs that increase 26S proteasome activity have potential therapeutic applications in the treatment of neurodegenerative diseases. A chemical genetics screen of over 2,750 compounds using a proteasome activity probe as a readout in a high-throughput live-cell fluorescence-activated cell sorting-based assay revealed more than ten compounds that increase proteasome activity, with the p38 MAPK inhibitor PD169316 being one of the most potent ones. Genetic and chemical inhibition of either p38 MAPK, its upstream regulators, ASK1 and MKK6, and downstream target, MK2, enhance proteasome activity...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28379698/chemically-induced-degradation-of-sirtuin-2-sirt2-by-a-proteolysis-targeting-chimera-protac-based-on-sirtuin-rearranging-ligands-sirreals
#19
Matthias Schiedel, Daniel Herp, Sören Hammelmann, Sören Swyter, Attila Lehotzky, Dina Robaa, Judit Oláh, Judit Ovádi, Wolfgang Sippl, Manfred Jung
Here we report the development of a proteolysis targeting chimera (PROTAC) based on the combination of the unique features of the sirtuin rearranging ligands (SirReals) as highly potent and isotype-selective Sirt2 inhibitors with thalidomide, a bona fide cereblon ligand. For the first time, we report the formation of a PROTAC by Cu(I)-catalyzed cycloaddition of a thalidomide-derived azide to an alkynylated inhibitor. This thalidomide-derived azide as well as the highly versatile linking strategy can be readily adapted to alkynylated ligands of other targets...
April 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28378579/a-click-chemistry-platform-for-the-rapid-synthesis-of-bispecific-molecules-for-inducing-protein-degradation
#20
Ryan P Wurz, Ken Dellamaggiore, Hannah Dou, Noelle Javier, Mei-Chu Lo, John D McCarter, Dane Mohl, Christine Sastri, J Russell Lipford, Victor J Cee
Proteolysis targeting chimeras (PROTACs) are bispecific molecules containing a target protein binder and an ubiquitin ligase binder connected by a linker. By recruiting an ubiquitin ligase to a target protein, PROTACs promote ubiquitination and proteasomal degradation of the target protein. The generation of effective PROTACs depends on the nature of the protein/ligase ligand pair, linkage site, linker length, and linker composition, all of which have been difficult to address in a systematic way. Herein, we describe a "click chemistry" approach for the synthesis of PROTACs...
April 5, 2017: Journal of Medicinal Chemistry
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