Abstract:
:The integrated stress response comprises multiple signaling pathways for detecting and responding to cellular stress that converge at a single event-the phosphorylation of Ser51 on the α-subunit of eukaryotic translation initiation factor 2 (eIF2α). Phosphorylation of eIF2α (eIF2α-P) results in attenuation of global protein synthesis via the inhibitory effects of eIF2α-P on eIF2B, the guanine exchange factor (GEF) for eIF2. Herein we describe structure-activity relationship (SAR) studies of bis-O-arylglycolamides, first-in-class integrated stress response inhibitors (ISRIB). ISRIB analogues make cells insensitive to the effects of eIF2α-P by activating the GEF activity of eIF2B and allowing global protein synthesis to proceed with residual unphosphorylated eIF2α. The SAR studies described herein support the proposed pharmacology of ISRIB analogues as binding across a symmetrical protein-protein interface formed between protein subunits of the dimeric eIF2B heteropentamer.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Hearn BR,Jaishankar P,Sidrauski C,Tsai JC,Vedantham P,Fontaine SD,Walter P,Renslo ARdoi
10.1002/cmdc.201500483subject
Has Abstractpub_date
2016-04-19 00:00:00pages
870-80issue
8eissn
1860-7179issn
1860-7187journal_volume
11pub_type
杂志文章相关文献
ChemMedChem文献大全abstract::A historical overview of key events that led, 50 years ago, to the foundation of the European Federation for Medicinal Chemistry (EFMC), and the impact this had on promoting and structuring medicinal chemistry as a discipline in Europe. EFMC, together with the growing number of newly established national medicinal che...
journal_title:ChemMedChem
pub_type: 社论
doi:10.1002/cmdc.202000691
更新日期:2020-12-15 00:00:00
abstract::Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblast...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700629
更新日期:2018-01-22 00:00:00
abstract::Over the past few years, the number of people diagnosed with type 2 diabetes has increased owing to an unhealthy diet, a limited amount of exercise, and obesity. The search for novel and efficient antidiabetes agents has become an urgent task for scientists. Among the antidiabetes drugs, α-glucosidase inhibitor drugs ...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.201700216
更新日期:2017-06-07 00:00:00
abstract::Together with estrogen receptors ERα and ERβ, the G protein-coupled estrogen receptor (GPER) mediates important pathophysiological signaling pathways induced by estrogens and is currently regarded as a promising target for ER-negative (ER-) and triple-negative (TN) breast cancer. Only a few selective GPER modulators h...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700145
更新日期:2017-08-22 00:00:00
abstract::Global pharmaceutical and biotechnology companies have been building increasingly on the skills and services offered by Indian biotech companies through strategic collaborative partnerships and alliances to fuel their in-house discovery and development pipelines. With the exception of generic press releases, however, ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300341
更新日期:2014-01-01 00:00:00
abstract::Compound 11 (3-(benzyloxy)-1'-methyl-1'-azonia-4H-1'-azaspiro[isoxazole-5,3'-bicyclo[2.2.2]octane] iodide) was selected from a previous set of nicotinic ligands as a suitable model compound for the design of new silent agonists of α7 nicotinic acetylcholine receptors (nAChRs). Silent agonists evoke little or no channe...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700162
更新日期:2017-08-22 00:00:00
abstract::We synthesized potential inhibitors of farnesyl diphosphate synthase (FPPS), undecaprenyl diphosphate synthase (UPPS), or undecaprenyl diphosphate phosphatase (UPPP), and tested them in bacterial cell growth and enzyme inhibition assays. The most active compounds were found to be bisphosphonates with electron-withdraw...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600343
更新日期:2016-10-06 00:00:00
abstract::Herein we describe the synthesis and biological evaluation of a series of novel benzothiazoles based on a diaryl urea scaffold previously reported in some allosteric chemokine receptor 2 (CXCR2) inhibitors. From a library of 41 new compounds, 17 showed significant inhibition of CXCR2, with IC50 values less than 10 μm ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700229
更新日期:2017-07-06 00:00:00
abstract::Drugs may have polypharmacological phenomena, that is, in addition to the desired target, they may also bind to many undesired or unknown physiological targets. As a result, they often exert side effects. In some cases, off-target interactions may lead to drug repositioning or to explaining a drug's mode of action. He...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500123
更新日期:2015-07-01 00:00:00
abstract::The less polar π-surface of protein amide groups is exposed in many receptor binding sites, either as part of the backbone or in Gln/Asn side chains. Using quantum chemical calculations and Protein Data Bank (PDB) searches on model systems, we investigate the energetics and geometric preferences for the stacking on am...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200512
更新日期:2013-03-01 00:00:00
abstract::Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis belong to a group of infectious diseases known as neglected tropical diseases and are induced by infection with protozoan parasites named trypanosomatids. Drugs in current use have several limitations, and therefore new candidate drugs are required...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.201700259
更新日期:2017-08-22 00:00:00
abstract::Tau-tubulin kinase 1 (TTBK1) is a serine/threonine/tyrosine kinase that putatively phosphorylates residues including S422 in tau protein. Hyperphosphorylation of tau protein is the primary cause of tau pathology and neuronal death associated with Alzheimer's disease. A library of 12 truncation variants comprising the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300274
更新日期:2013-11-01 00:00:00
abstract::Cancer cells express high levels of CK2, and its inhibition leads to apoptosis. CK2 has therefore emerged as a new drug target for cancer therapy. A biligand inhibitor ARC-772 was constructed by conjugating 4-(2-amino-1,3-thiazol-5-yl)benzoic acid and a carboxylate-rich peptoid. ARC-772 was found to bind CK2 with a Kd...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700457
更新日期:2017-10-20 00:00:00
abstract::New geiparvarin derivatives modified at the unsaturated alkenyloxy bridge, where a hydrogen atom replaces the 3'-methyl group, were synthesized and evaluated against a panel of human tumor cell lines in vitro. These compounds demonstrated an increase in growth inhibitory activity relative to the parent compound, geipa...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900009
更新日期:2009-05-01 00:00:00
abstract::Disturbances of neutrotransmission at the dopamine D3 receptor are related to several neuropsychiatric diseases and in particular to drug addiction. Herein, we report the computer-assisted prediction of D3 selectivities of new fluoroalkoxy-substituted receptor ligands by means of 3D-QSAR analysis. As close analogues o...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200700327
更新日期:2008-05-01 00:00:00
abstract::Different Mannich base derivatives have been studied with the aim of addressing the poor aqueous solubility of the recently disclosed 6-phenethyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (1), a human butyrylcholinesterase inhibitor (hBChE, IC50 13 nM) and protective agent in NMDA-induced neurotoxicity, in in vi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000583
更新日期:2020-11-06 00:00:00
abstract::The renin angiotensin aldosterone system (RAAS) is a hormonal cascade involved in the regulation of blood pressure and electrolyte balance, and represents a common target for the treatment of various diseases including hypertension, heart failure, and diabetes. Herein we present a novel 18 F-labeled derivative of the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800638
更新日期:2018-12-06 00:00:00
abstract::From insects to cancer: N-Cyano sulfoximines were evaluated for COX inhibition and antiproliferative activity against a panel of cancer cell lines. The most active compound exhibited potent COX-2 inhibition, some selectivity for COX-2 over COX-1, only slight cytotoxicity towards healthy cells (HaCaT skin cells), and n...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200403
更新日期:2013-02-01 00:00:00
abstract::Vascular endothelial growth factor receptor 2 (VEGFR2) has been proven to play a major role in the regulation of tumor angiogenesis. A series of novel glycyrrhetic acid derivatives were synthesized and evaluated for their VEGFR2 inhibitory activity as well as their antiproliferative properties against four cancer cell...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700271
更新日期:2017-07-06 00:00:00
abstract::A small library of 17 organoruthenium compounds with the general formula [RuII (fcl)(chel)(L)]n+ (in which fcl=face capping ligand, chel=chelating bidentate ligand, and L=monodentate ligand) were screened for inhibitory activity against cholinesterases and glutathione-S-transferases of human and animal origins. Compou...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800432
更新日期:2018-10-22 00:00:00
abstract::The DATA chelators are a novel class of tri-anionic ligands based on 6-amino-1,4-diazepine-triacetic acid, which have been introduced recently for the chelation of (68)Ga. Compared with macrocyclic chelators based on the cyclen scaffold (i.e., DOTA, DO3A, and DO2A derivatives), DATA chelators undergo quantitative radi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500092
更新日期:2015-06-01 00:00:00
abstract::Given the worldwide spread of bacterial drug resistance, there is an urgent need to develop new compounds that exhibit potent antibacterial activity and that are unimpaired by this phenomenon. Quaternary ammonium compounds have been used for many years as disinfectants, but recent advances have shown that polycationic...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900151
更新日期:2019-07-03 00:00:00
abstract::Two libraries, each consisting of 48 16beta-aminopropyl estradiol derivatives, phenols and sulfamates, respectively, were synthesized by solid-phase parallel chemistry through a seven-step reaction sequence. Following the attachment of a C18-steroid sulfamate precursor on a trityl chloride resin, diversity elements we...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600071
更新日期:2006-11-01 00:00:00
abstract::Targeting the biosynthetic pathway of neuroactive steroids with specific 18 kDa translocator protein (TSPO) ligands may be a viable therapeutic approach for a variety of neurodegenerative and neuropsychiatric diseases. However, the lack of correlation between binding affinity and in vitro steroidogenic efficacy has li...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700220
更新日期:2017-08-22 00:00:00
abstract::A facile protocol that enables synthetic interconversion of CUR-BF2 and CUR compounds is described that significantly widens the preparative scope of curcuminoids, providing access to larger libraries of compounds, thus enabling comparative antiproliferative and apoptotic study of a larger library of synthetic analogs...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900640
更新日期:2020-02-17 00:00:00
abstract::The global fight to stop tuberculosis (TB) remains a great challenge, particularly with the increase in drug-resistant strains and a lack of funding to support the development of new treatments. To bolster a precarious drug pipeline, we prepared a focused panel of eight pentafluorosulfanyl (SF5 ) compounds which were ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700170
更新日期:2017-07-20 00:00:00
abstract::Drug metabolism, toxicity, and their interaction profiles are major issues in the drug-discovery and lead-optimization processes. The cytochromes P450 (CYPs) 2D6 and 2C9 are enzymes involved in the oxidative metabolism of a majority of marketed drugs. Therefore, the prediction of the binding affinity towards CYP2D6 an...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000358
更新日期:2010-12-03 00:00:00
abstract::Herein we describe the synthesis and conformational analysis of a series of bicyclic thymidine derivatives and their evaluation as inhibitors of thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), based on previously discovered bicyclic sugar nucleosides. With a K(i) value of 2.3 microm, 1-[3-amin...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600028
更新日期:2006-10-01 00:00:00
abstract::Histone deacetylases (HDACs) are promising drug targets for a variety of therapeutic applications. Herein we describe the design, synthesis, biological evaluation in cellular models of cancer, and preliminary drug metabolism and pharmacokinetic studies (DMPK) of a series of secondary and tertiary N-substituted 7-amino...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700449
更新日期:2017-12-19 00:00:00
abstract::A series of new substituted 7-phenyl-3H-pyrrolo[3,2-f]quinolin-9-ones were synthesized and evaluated for their antiproliferative activity. The most active derivatives showed high selectivity against human leukemia cell lines and potently inhibited their growth, with GI(50) values in the nanomolar range. The active com...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201000180
更新日期:2010-08-02 00:00:00