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https://www.readbyqxmd.com/read/29650462/thioamide-substitution-to-probe-the-hydroxyproline-recognition-of-vhl-ligands
#1
Pedro Soares, Xavier Lucas, Alessio Ciulli
Thioamide substitution influences hydrogen bond and n → π∗ interactions involved in the conformational stability of protein secondary structures and oligopeptides. Hydroxyproline is the key recognition element of small molecules targeting the von Hippel-Lindau (VHL) E3 ligase, which are of interest as probes of hypoxia signaling and ligands for PROTAC conjugation. We hypothesized that VHL ligands could be a privileged model system to evaluate the contribution of these interactions to protein:ligand complex formation...
March 23, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29627725/proteolysis-targeting-chimeras-protacs-of-anaplastic-lymphoma-kinase-alk
#2
Chengwei Zhang, Xiao-Ran Han, Xiaobao Yang, Biao Jiang, Jing Liu, Yue Xiong, Jian Jin
Anaplastic lymphoma kinase (ALK) activation has been associated with many types of human cancer. Significant efforts have been devoted to the development of ALK inhibitors to antagonize the kinase activity of ALK. Four ALK inhibitors have been approved by the FDA to date for treating patients with ALK-positive non-small cell lung cancers (NSCLC). However, drug resistance has been observed in the majority of patients treated with these inhibitors. New therapeutic strategies (e.g., compounds with novel mechanisms of action) are needed to overcome the drug resistance issue...
March 27, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29625382/phthalimide-conjugations-for-the-degradation-of-oncogenic-pi3k
#3
Wenlu Li, Chunmei Gao, Lei Zhao, Zigao Yuan, Yuzong Chen, Yuyang Jiang
PI3K/Akt/mTOR pathway is crucial for carcinogenesis and its inhibitors have made a great progress in cancer treatment. However, there is still a great developing space for PI3K inhibitors as the acquired drug resistance hindered their application in clinical. Proteolysis-targeting chimeras (PROTACs) with the potential to handle the challenges faced in drug development could be an alternative therapeutic strategy. Moreover, the past two years have witnessed remarkable advances in the development of phthalimide conjugation as a strategy for the degradation instead of inhibition of the targets, including BET family proteins, Sirtuin 2, CDK 9, Smad 3, and BCR-ABL proteins...
March 26, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29581547/protein-targeting-chimeric-molecules-specific-for-bromodomain-and-extra-terminal-motif-family-proteins-are-active-against-pre-clinical-models-of-multiple-myeloma
#4
Xiaohui Zhang, Hans C Lee, Fazal Shirazi, Veerabhadran Baladandayuthapani, Heather Lin, Isere Kuiatse, Hua Wang, Richard J Jones, Zuzana Berkova, Ram Kumar Singh, Jing Lu, Yimin Qian, Kanak Raina, Kevin G Coleman, Craig M Crews, Bingzong Li, Huihan Wang, Yared Hailemichael, Sheeba K Thomas, Zhiqiang Wang, R Eric Davis, Robert Z Orlowski
Bromodomain and extraterminal (BET) domain containing protein (BRD)-4 modulates the expression of oncogenes such as c-myc, and is a promising therapeutic target in diverse cancer types. We performed pre-clinical studies in myeloma models with bi-functional protein-targeting chimeric molecules (PROTACs) which target BRD4 and other BET family members for ubiquitination and proteasomal degradation. PROTACs potently reduced the viability of myeloma cell lines in a time-dependent and concentration-dependent manner associated with G0 /G1 arrest, reduced levels of CDKs 4 and 6, increased p21 levels, and induction of apoptosis...
March 27, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29473971/protacs-an-emerging-targeting-technique-for-protein-degradation-in-drug-discovery
#5
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...
April 2018: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/29453240/arvinas-pfizer-team-up-on-protacs
#6
(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.
April 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29448097/selective-degradation-of-bet-proteins-with-dbet1-a-proteolysis-targeting-chimera-potently-reduces-pro-inflammatory-responses-in-lipopolysaccharide-activated-microglia
#7
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 26, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29407955/discovery-of-a-keap1-dependent-peptide-protac-to-knockdown-tau-by-ubiquitination-proteasome-degradation-pathway
#8
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 25, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29351837/try-me-promiscuous-inhibitors-still-allow-for-selective-targeted-protein-degradation
#9
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
https://www.readbyqxmd.com/read/29198160/targeting-oncoproteins-for-degradation-by-small-molecules-in-myeloid-leukemia
#10
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
https://www.readbyqxmd.com/read/29144739/protac-induced-protein-degradation-in-drug-discovery-breaking-the-rules-or-just-making-new-ones
#11
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
https://www.readbyqxmd.com/read/29129718/lessons-in-protac-design-from-selective-degradation-with-a-promiscuous-warhead
#12
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...
January 18, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29129716/the-advantages-of-targeted-protein-degradation-over-inhibition-an-rtk-case-study
#13
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...
January 18, 2018: 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
#14
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
#15
REVIEW
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
https://www.readbyqxmd.com/read/29018234/homo-protacs-bivalent-small-molecule-dimerizers-of-the-vhl-e3-ubiquitin-ligase-to-induce-self-degradation
#16
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
#17
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
#18
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
#19
Pedro Soares, Morgan S Gadd, Julianty Frost, Carles Galdeano, Lucy 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...
January 25, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28833638/design-synthesis-and-characterization-of-brequinar-conjugates-as-probes-to-study-dhodh-inhibition
#20
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...
October 9, 2017: Chemistry: a European Journal
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