Read by QxMD icon Read


Xavier Lucas, Alessio Ciulli
The ubiquitin-proteasome system is a master regulator of protein homeostasis, by which proteins are initially targeted for poly-ubiquitination by E3 ligases and then degraded into short peptides by the proteasome. Nature evolved diverse peptidic motifs, termed degrons, to signal substrates for degradation. We discuss degrons of the N-end rule pathway and also degrons characterized by post-translational modifications, including phosphorylation and hydroxylation. In each case we detail the structural basis of E3 ligase:degron recognition and small-molecule mimicry approaches that disrupt those protein-protein interactions...
January 25, 2017: Current Opinion in Structural Biology
Honorine Lebraud, David J Wright, Christopher N Johnson, Tom D Heightman
Selective degradation of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic intervention. Current PROTAC molecules incorporate a ligand for the target protein, a linker, and an E3 ubiquitin ligase recruiting group, which bring together target protein and ubiquitinating machinery. Such hetero-bifunctional molecules require significant linker optimization and possess high molecular weight, which can limit cellular permeation, solubility, and other drug-like properties...
December 28, 2016: ACS Central Science
D T Saenz, W Fiskus, Y Qian, T Manshouri, K Rajapakshe, K Raina, K G Coleman, A P Crew, A Shen, C P Mill, B Sun, P Qiu, T M Kadia, N Pemmaraju, C DiNardo, M-S Kim, A J Nowak, C Coarfa, C M Crews, S Verstovsek, K N Bhalla
The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Whereas the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells...
January 2, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Maria Pia Abruzzese, Maria Teresa Bilotta, Cinzia Fionda, Alessandra Zingoni, Alessandra Soriani, Elisabetta Vulpis, Cristiana Borrelli, Beatrice Zitti, Maria Teresa Petrucci, Maria Rosaria Ricciardi, Rosa Molfetta, Rossella Paolini, Angela Santoni, Marco Cippitelli
BACKGROUND: Anti-cancer immune responses may contribute to the control of tumors after conventional chemotherapy, and different observations have indicated that chemotherapeutic agents can induce immune responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of natural killer (NK) cells in immune responses toward multiple myeloma (MM), and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer...
December 1, 2016: Journal of Hematology & Oncology
Ashton C Lai, Craig M Crews
Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function, and this approach typically precludes targeting proteins that lack such amenable sites. Furthermore, high systemic drug exposures may be needed to maintain sufficient target inhibition in vivo, increasing the risk of undesirable off-target effects. Induced protein degradation is an alternative approach that is event-driven: upon drug binding, the target protein is tagged for elimination...
2017: Nature Reviews. Drug Discovery
Jasmin Lohbeck, Aubry K Miller
The use of small molecules to regulate cellular levels of specific proteins is poised to become a powerful technique in the coming years. Critical to the success of any project utilizing such an approach will be the ability to synthesize libraries of candidate small molecules for testing in cellular systems. Herein, we describe a practical synthesis of a phthalimide-based scaffold, which can be easily diversified to make Cereblon-targeting PROTACs. We demonstrate the effectiveness of this approach by synthesizing a 'PROTAC toolbox' of four amines which can be coupled to inhibitors in a straightforward manner...
September 19, 2016: Bioorganic & Medicinal Chemistry Letters
Xin Wang, Shaozhen Feng, Jinjin Fan, Xiaoyan Li, Qiong Wen, Ning Luo
PURPOSE: Smad3 is a critical signaling protein in renal fibrosis. Proteolysis targeting chimeric molecules (PROTACs) are small molecules designed to degrade target proteins via ubiquitination. They have three components: (1) a recognition motif for E3 ligase; (2) a linker; and (3) a ligand for the target protein. We aimed to design a new PROTAC to prevent renal fibrosis by targeting Smad3 proteins and using hydroxylated pentapeptide of hypoxia-inducible factor-1α as the recognition motif for von Hippel-Lindau (VHL) ubiquitin ligase (E3)...
September 15, 2016: Biochemical Pharmacology
Kanak Raina, Jing Lu, Yimin Qian, Martha Altieri, Deborah Gordon, Ann Marie K Rossi, Jing Wang, Xin Chen, Hanqing Dong, Kam Siu, James D Winkler, Andrew P Crew, Craig M Crews, Kevin G Coleman
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...
June 28, 2016: Proceedings of the National Academy of Sciences of the United States of America
Ryan K Henning, Joseph O Varghese, Samir Das, Arundhati Nag, Grace Tang, Kevin Tang, Alexander M Sutherland, James R Heath
Abnormal signaling of the protein kinase Akt has been shown to contribute to human diseases such as diabetes and cancer, but Akt has proven to be a challenging target for drugging. Using iterative in situ click chemistry, we recently developed multiple protein-catalyzed capture (PCC) agents that allosterically modulate Akt enzymatic activity in a protein-based assay. Here, we utilize similar PCCs to exploit endogenous protein degradation pathways. We use the modularity of the anti-Akt PCCs to prepare proteolysis targeting chimeric molecules that are shown to promote the rapid degradation of Akt in live cancer cells...
April 2016: Journal of Peptide Science: An Official Publication of the European Peptide Society
Momar Toure, Craig M Crews
The current inhibitor-based approach to therapeutics has inherent limitations owing to its occupancy-based model: 1) there is a need to maintain high systemic exposure to ensure sufficient in vivo inhibition, 2) high in vivo concentrations bring potential for off-target side effects, and 3) there is a need to bind to an active site, thus limiting the drug target space. As an alternative, induced protein degradation lacks these limitations. Based on an event-driven model, this approach offers a novel catalytic mechanism to irreversibly inhibit protein function by targeting protein destruction through recruitment to the cellular quality control machinery...
February 5, 2016: Angewandte Chemie
Ashton C Lai, Momar Toure, Doris Hellerschmied, Jemilat Salami, Saul Jaime-Figueroa, Eunhwa Ko, John Hines, Craig M Crews
Proteolysis Targeting Chimera (PROTAC) technology is a rapidly emerging alternative therapeutic strategy with the potential to address many of the challenges currently faced in modern drug development programs. PROTAC technology employs small molecules that recruit target proteins for ubiquitination and removal by the proteasome. The synthesis of PROTAC compounds that mediate the degradation of c-ABL and BCR-ABL by recruiting either Cereblon or Von Hippel Lindau E3 ligases is reported. During the course of their development, we discovered that the capacity of a PROTAC to induce degradation involves more than just target binding: the identity of the inhibitor warhead and the recruited E3 ligase largely determine the degradation profiles of the compounds; thus, as a starting point for PROTAC development, both the target ligand and the recruited E3 ligase should be varied to rapidly generate a PROTAC with the desired degradation profile...
January 11, 2016: Angewandte Chemie
Nobumichi Ohoka, Norihito Shibata, Takayuki Hattori, Mikihiko Naito
Selective degradation of pathogenic proteins by small molecules in cells is a novel approach for development of therapeutic agents against various diseases, including cancer. We and others have developed a protein knockdown technology with a series of hybrid small compounds, called SNIPERs (Specific and Nongenetic IAP-dependent Protein ERasers); and peptidic chimeric molecules, called PROTACs (proteolysis-targeting chimeric molecules), which induce selective degradation of target proteins via the ubiquitin-proteasome pathway...
2016: Current Cancer Drug Targets
Raymond J Deshaies
No abstract text is available yet for this article.
November 2015: Nature Chemical Biology
Raymond J Deshaies
No abstract text is available yet for this article.
September 2015: Nature Chemical Biology
Daniel P Bondeson, Alina Mares, Ian E D Smith, Eunhwa Ko, Sebastien Campos, Afjal H Miah, Katie E Mulholland, Natasha Routly, Dennis L Buckley, Jeffrey L Gustafson, Nico Zinn, Paola Grandi, Satoko Shimamura, Giovanna Bergamini, Maria Faelth-Savitski, Marcus Bantscheff, Carly Cox, Deborah A Gordon, Ryan R Willard, John J Flanagan, Linda N Casillas, Bartholomew J Votta, Willem den Besten, Kristoffer Famm, Laurens Kruidenier, Paul S Carter, John D Harling, Ian Churcher, Craig M Crews
The current predominant therapeutic paradigm is based on maximizing drug-receptor occupancy to achieve clinical benefit. This strategy, however, generally requires excessive drug concentrations to ensure sufficient occupancy, often leading to adverse side effects. Here, we describe major improvements to the proteolysis targeting chimeras (PROTACs) method, a chemical knockdown strategy in which a heterobifunctional molecule recruits a specific protein target to an E3 ubiquitin ligase, resulting in the target's ubiquitination and degradation...
August 2015: Nature Chemical Biology
Dennis L Buckley, Kanak Raina, Nicole Darricarrere, John Hines, Jeffrey L Gustafson, Ian E Smith, Afjal H Miah, John D Harling, Craig M Crews
Small molecule-induced protein degradation is an attractive strategy for the development of chemical probes. One method for inducing targeted protein degradation involves the use of PROTACs, heterobifunctional molecules that can recruit specific E3 ligases to a desired protein of interest. PROTACs have been successfully used to degrade numerous proteins in cells, but the peptidic E3 ligase ligands used in previous PROTACs have hindered their development into more mature chemical probes or therapeutics. We report the design of a novel class of PROTACs that incorporate small molecule VHL ligands to successfully degrade HaloTag7 fusion proteins...
August 21, 2015: ACS Chemical Biology
Jing Lu, Yimin Qian, Martha Altieri, Hanqing Dong, Jing Wang, Kanak Raina, John Hines, James D Winkler, Andrew P Crew, Kevin Coleman, Craig M Crews
BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt's lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest antiproliferative activity, and lack of apoptotic induction. To address these limitations we designed ARV-825, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested...
June 18, 2015: Chemistry & Biology
Michael Zengerle, Kwok-Ho Chan, Alessio Ciulli
The Bromo- and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation, epigenetics, and cancer and are the targets of pan-BET selective bromodomain inhibitor JQ1. However, the lack of intra-BET selectivity limits the scope of current inhibitors as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We designed Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins...
August 21, 2015: ACS Chemical Biology
Wen Tang, Yu Wang, Xinyan Zhao, Xiaoming Wang, Tao Zhang, Xiaojuan Ou, Weiling Shou, Hong You, Jidong Jia
OBJECTIVES: Hypercoagulability, hemodynamic changes, and endothelial injury are the three major contributors to the development of thrombosis. However, the role of hypercoagulability in portal vein thrombosis (PVT) in liver cirrhosis is still controversial. The aim of this study is to elucidate the relationship between procoagulant imbalance and PVT in patients with liver cirrhosis. METHODS: This study included 151 patients with cirrhosis with (n=20) or without PVT (n=131)...
June 2015: European Journal of Gastroenterology & Hepatology
P Cookson, A Lawrie, L Green, E Dent, S Proffitt, S Bashir, S Thomas, R Cardigan
BACKGROUND: We assessed the haemostatic capacity of thawed plasma produced after ambient storage of whole blood for 24 h (RTFP24), and the supernatant of buffy-coat derived platelet concentrates (PC). METHODS: Platelet concentrates (n = 20) were tested on days 1, 5 and 7 of storage at 22°C and RTFP24 (n = 10) immediately following thawing and after 4 and 6 days storage at 4°C. Coagulation factor activity, thrombin generation ± an activator of protein C (PROTAC) and rotational thromboelastometry (ROTEM) were assessed...
February 2015: Vox Sanguinis
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"