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 value of 0.3 nm and showed remarkable CK2 inhibitory selectivity in a panel of 140 protein kinases (Gini coefficient: 0.75 at c=100 nm). ARC-775, the acetoxymethyl ester prodrug of ARC-772, was efficiently taken up by cells. Once internalized, the inhibitor is activated by cellular esterase activity. In HeLa cancer cells ARC-775 was found to activate caspase-3 (an apoptosis marker) at sub-micromolar concentrations (EC50 =0.3 μm), a 20-fold lower extracellular concentration than CX-4945, the only CK2 inhibitor under clinical trials. At micromolar concentrations, ARC-775 was also found to inhibit ADP-induced aggregation of human platelets. The overall results of this study demonstrate that oligo-anionic biligand inhibitors have good potential for drug development.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Rahnel H,Viht K,Lavogina D,Mazina O,Haljasorg T,Enkvist E,Uri Adoi
10.1002/cmdc.201700457subject
Has Abstractpub_date
2017-10-20 00:00:00pages
1723-1736issue
20eissn
1860-7179issn
1860-7187journal_volume
12pub_type
杂志文章相关文献
ChemMedChem文献大全abstract::The consumption of Brassica vegetables provides beneficial effects through organic isothiocyanates (ITCs), products of the enzymatic hydrolysis of glucosinolate secondary metabolites. The ITC l-sulforaphane (l-SFN) is the principle agent in broccoli that demonstrates several modes of anticancer action. While the antic...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800348
更新日期:2018-08-20 00:00:00
abstract::Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impairments of the NO-sGC signaling pathway have been implicated in the pathogenesis of cardiovascular and other diseases. Direct stimulation of sGC represents a promising therapeutic strategy particularly for the treat...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900014
更新日期:2009-05-01 00:00:00
abstract::The tropical diseases human African trypanosomiasis, Chagas disease, and the various forms of leishmaniasis are caused by parasites of the family of trypanosomatids. These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report th...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800067
更新日期:2018-05-08 00:00:00
abstract::Up to 45 % of deaths in developed nations can be attributed to chronic fibroproliferative diseases, highlighting the need for effective therapies. The RGD (Arg-Gly-Asp) integrin αvβ1 was recently investigated for its role in fibrotic disease, and thus warrants therapeutic targeting. Herein we describe the identificati...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900359
更新日期:2019-07-17 00:00:00
abstract::Silent Night: Antagonism of the orexin (or hypocretin) system has recently been identified as a novel mechanism for the treatment of insomnia. Herein, we describe discovery of a dual (OX(1)R/OX(2)R) orexin receptor antagonist featuring a 1,4-diazepane central constraint that blocks orexin signaling in vivo. In telemet...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900069
更新日期:2009-07-01 00:00:00
abstract::Over the years, the 2-substituted imidazoline nucleus has been demonstrated to be a bioversatile structural motif. In this study, novel imidazoline derivatives bearing a 3- and/or 4-hydroxy- or methoxy-substituted phenyl ring, linked by an ethylene bridge to position 2 of an N-benzyl- or N-phenethyl-substituted imidaz...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600022
更新日期:2016-08-19 00:00:00
abstract::Targeting LRH-1: Virtual screening and molecular modeling were used to identify novel antagonists of liver receptor homolog-1 (LRH-1), an emerging therapeutic target for breast cancer. Hit compounds were synthesized and biologically assayed, and the preliminary results suggest that raloxifene-based analogues, substitu...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200307
更新日期:2012-11-01 00:00:00
abstract::Identification of potent agonists of odorant receptors (ORs), a major class of G protein-coupled receptors, remains challenging due to complex receptor-ligand interactions. ORs are present in both olfactory and non-chemosensory tissues, indicating roles beyond odor detection that may include modulating physiological f...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600612
更新日期:2017-04-06 00:00:00
abstract::For (64) Cu radiolabeling of biomolecules to be used as in vivo positron emission tomography (PET) imaging agents, various chelators are commonly applied. It has not yet been determined which of the most potent chelators--NODA-GA ((1,4,7-triazacyclononane-4,7-diyl)diacetic acid-1-glutaric acid), CB-TE2A (2,2'-(1,4,8,1...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500132
更新日期:2015-07-01 00:00:00
abstract::Using the original approach, a series of metallated N-confused porphyrins and metallated porphyrins have been synthesized and characterized. For all the synthesized porphyrins, in vitro studies of cytotoxic activity against K562, U937, HL-60, Jurkat, A549 and HeLa cancer cell lines, the ability to induce apoptosis and...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900633
更新日期:2020-04-03 00:00:00
abstract::A small set of aggrecanase inhibitors based on the pyrrolo[3,4-c]quinolin-1-one or oxoisoindoline frameworks bearing a 4-(benzyloxy)phenyl substituent and different zinc binding groups were rationally designed and evaluated in silico by docking studies using the crystal structure of the ADAMTS-5 catalytic domain (PDB ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900523
更新日期:2010-05-03 00:00:00
abstract::A group of acidic nucleosides were synthesized to develop a new class of ribonuclease A (RNase A) inhibitors. Our recent study on carboxymethylsulfonyl-modified nucleosides revealed some interesting results in RNase A inhibition. This positive outcome triggered an investigation of the role played by secondary sugar hy...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402179
更新日期:2014-09-01 00:00:00
abstract::The serotonin transporter (SERT) is one of the neurotransmitter transporters that plays a critical role in the regulation of endogenous amine concentrations and therefore is an important target for therapeutic agents affecting the central nervous system. The recently published, high resolution X-ray structure of the c...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600242
更新日期:2007-06-01 00:00:00
abstract::The development and progression of chronic complications in diabetic patients, such as retinopathy, nephropathy, neuropathy, cataracts, and stroke, are related to the activation and/or overexpression of aldose reductase (ALR2), which is a member of the aldo-keto reductase superfamily. A structure-activity relationship...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200386
更新日期:2013-04-01 00:00:00
abstract::In solution, amphoteric compounds exist in anionic, uncharged, zwitterionic and cationic forms. The importance of zwitterionic drugs is currently under-represented in the literature. Herein, the acid-base parameters, lipophilicity and solubility of such compounds are discussed to deepen the molecular-level understandi...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.202000164
更新日期:2020-07-03 00:00:00
abstract::An efficient stereocontrolled synthesis afforded alkoxymethylenephosphonate (MP) analogues of lysophosphatidic acid (LPA) and phosphatidic acid (PA). The pharmacological properties of MP-LPA and MP-PA analogues were characterized for LPA receptor subtype-specific agonist and antagonist activity using Ca(2+)-mobilizati...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200700111
更新日期:2007-12-01 00:00:00
abstract::Detailed information on the metabolic fate of lead compounds can be a powerful tool for an informed approach to the stabilization of metabolically labile compounds in the lead optimization phase. The combination of high performance liquid chromatography (HPLC) with nuclear magnetic resonance (NMR) spectroscopy and mas...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200700203
更新日期:2008-01-01 00:00:00
abstract::Meridional rhodium(III) polypyridyl complexes of the type mer-[RhX(3)(DMSO)(pp)] (X=Cl, pp=phen 1, dpq 2, dppz 3; X=Br, pp=phen 4) represent a promising class of potent cytostatic agents for the treatment of lymphoma and leukemia. Exposure of their DMSO solutions to light leads to slow isomerization to mixtures of the...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200800311
更新日期:2009-02-01 00:00:00
abstract::Having recently identified a so-far unexplored area adjacent to the known binding site of allosteric mitogen-activated protein kinase kinase (MEK) inhibitors, we now report an extension of these studies by combining our new side chains with different MEK inhibitor cores in a modular manner. Replacement of the amide he...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500442
更新日期:2015-12-01 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::Schistosomiasis is a neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy relies on mass treatment with only one drug: praziquantel. Based on the 3-chlorobenzothiophene-2-hydroxamic acid J1075, a series of hydroxamic acids with different scaffolds were prep...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800238
更新日期:2018-08-10 00:00:00
abstract::Apelin is the endogenous ligand of the APJ receptor, a member of the G-protein-coupled receptor family. The apelin-APJ complex has been detected in many tissues and is emerging as a promising target for several pathophysiological conditions. There is currently little information on the structure-activity relationship ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201100492
更新日期:2012-02-06 00:00:00
abstract::The protozoan parasite Plasmodium falciparum causes the most severe and prevailing form of malaria in sub-Saharan Africa. Previously, we identified the plasmodial lactate transporter, PfFNT, a member of the microbial formate-nitrite transporter family, as a novel antimalarial drug target. With the pentafluoro-3-hydrox...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000952
更新日期:2020-12-18 00:00:00
abstract::The CXCR3 receptor, a class A G protein-coupled receptor (GPCR), is involved in the regulation and trafficking of various immune cells. CXCR3 antagonists have been proposed to be beneficial for the treatment of a wide range of disorders including but not limited to inflammatory and autoimmune diseases. The structure-b...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500573
更新日期:2016-03-17 00:00:00
abstract::The role of beta-aminovinyl ketones as synthetic intermediates has been well categorised, but recent developments have shown an interesting array of applications and new chemotherapeutic potential, both in the preparation of biologically active heterocycles and as pharmacophores in their own right.Medicinal chemists a...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.200900006
更新日期:2009-07-01 00:00:00
abstract::Modulating epigenetic mechanisms in malarial parasites is an emerging avenue for the discovery of novel antimalarial drugs. Previously we demonstrated the potent in vitro and in vivo antimalarial activity of (1-benzyl-4-piperidyl)[6,7-dimethoxy-2-(4-methyl-1,4-diazepin-1-yl)-4-quinazolinyl]amine (BIX01294; 1), a known...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402098
更新日期:2014-10-01 00:00:00
abstract::Targeting protein-protein interactions, such as the HIV-1 gp120-CD4 interface, has become a cutting-edge approach in the current drug discovery scenario. Many small molecules have been developed so far as inhibitors of the interaction between CD4 and HIV-1 gp120. However, due to a variety of reasons such as solubility...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200584
更新日期:2013-03-01 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::Progesterone plays an important role in the female reproductive system. However, there is also evidence that gynecologic disorders/diseases such as uterine fibroids and endometriosis are progesterone-dependent. Steroidal and non-steroidal selective progesterone receptor modulators (SPRMs) have shown potential for the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800487
更新日期:2018-11-06 00:00:00
abstract::Over the years, a number of dimensionality reduction techniques have been proposed and used in chemoinformatics to perform nonlinear mappings. In this study, four representatives of nonlinear dimensionality reduction methods related to two different families were analyzed: distance-based approaches (Isomap and Diffusi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201400027
更新日期:2014-05-01 00:00:00