Abstract:
:Retinoid X receptor-alpha (RXRα) is implicated in the regulation of many biological processes and also represents a unique intracellular target for pharmacologic interventions. Efforts on discovery of small molecules targeting RXRα have been primarily focused on the molecules that bind to its classical ligand-binding pocket (LBP). Here, we report the identification and characterization of a new RXRα transcriptional antagonist by using structure-based virtual screening. The new antagonist binds with submicromolar affinity to RXRα (Kd = 4.88 × 10-7 M) and selectively inhibits RXRα transactivation. The compound does not bind to the LBP but to a hydrophobic groove on the surface of RXRα. The new compound also effectively suppresses AKT activation and promotes apoptosis of cancer cells in a RXRα-dependent manner by inhibiting tRXRα interaction with the p85α subunit of PI3K. Thus, the compound represents a new RXRα modulator that regulates the nongenomic actions of RXRα by surface binding.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Chen F,Liu J,Huang M,Hu M,Su Y,Zhang XKdoi
10.1021/ml5000405subject
Has Abstractpub_date
2014-05-14 00:00:00pages
736-741issue
7issn
1948-5875journal_volume
5pub_type
杂志文章abstract::Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction-reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compo...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.6b00119
更新日期:2016-06-02 00:00:00
abstract::Substitution of rigidified A3 adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-yl)ethynyl) or a 2-(4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl) group provides prolonged protection in a model of chronic neuropathic pain. These agonists contain a bicyclo[3.1.0]hexane ((N)-methanocarba) ring system in p...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00150
更新日期:2015-05-20 00:00:00
abstract::Minibodies show rapider blood clearance than IgGs due to smaller size that improves target-to-background ratio (TBR) in in vivo imaging. Additionally, the ability to activate an optical probe after binding to the target greatly improves the TBR. An optical imaging probe based on a minibody against prostate-specific me...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400533y
更新日期:2014-01-17 00:00:00
abstract::A series of fluorine-substituted monomeric and dimeric cRGD peptide derivatives, such as cRGD-ADIBOT-F (ADIBOT = azadibenzocyclooctatriazole), di-cRGD-ADIBOT-F, cRGD-PEG5-ADIBOT-F, and di-cRGD-PEG5-ADIBOT-F, were prepared by strain-promoted alkyne azide cycloaddition (SPAAC) reaction of the corresponding aza-dibenzocy...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500464f
更新日期:2015-02-06 00:00:00
abstract::Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00481
更新日期:2018-01-19 00:00:00
abstract::A series of TRPA1 antagonists is described which has as its core structure an indazole moiety. The physical properties and in vitro DMPK profiles are discussed. Good in vivo exposure was obtained with several analogs, allowing efficacy to be assessed in rodent models of inflammatory pain. Two compounds showed signific...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00140
更新日期:2017-05-18 00:00:00
abstract::Multitarget anti-inflammatory drugs interfering with the arachidonic acid cascade exhibit superior efficacy. In this study, a prototype dual inhibitor of soluble epoxide hydrolase (sEH) and LTA4 hydrolase (LTA4H) with submicromolar activity toward both targets has been designed and synthesized. Preliminary structure-a...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00330
更新日期:2019-10-30 00:00:00
abstract::DNA methylation is known as the prima donna epigenetic mark for its critical role in regulating local gene transcription. Changes in the landscape of DNA methylation across the genome occur during cellular transition, such as differentiation and altered neuronal plasticity, and become dysregulated in disease states su...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00474
更新日期:2019-01-31 00:00:00
abstract::Human mitogen-activated protein kinases (MAPK)-interacting kinases 1 and 2 (Mnk1/2) are promising anticancer targets. Mnks possess special insertions and a DFD-motif that are distinct from other kinases. Crystallographic studies of Mnk1/2 have revealed that the DFD-motif adopts the DFG/D-out conformation in which resi...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400145x
更新日期:2013-06-24 00:00:00
abstract::The self-assembly of amyloid proteins into β-sheet rich assemblies is associated with human amyloidoses including Alzheimer's disease, Parkinson's disease, and type 2 diabetes. An attractive therapeutic strategy therefore is to develop small molecules that would inhibit protein self-assembly. Natural polyphenols are p...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml300147m
更新日期:2012-08-28 00:00:00
abstract::The receptor for the neuropeptide relaxin 3, relaxin family peptide 3 (RXFP3) receptor, is an attractive pharmacological target for the control of eating, addictive, and psychiatric behaviors. Several structure-activity relationship studies on both human relaxin 3 (containing 3 disulfide bonds) and its analogue A2 (tw...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00456
更新日期:2020-10-22 00:00:00
abstract::Because of the promise of BCL-2 antagonists in combating chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), interest in additional selective antagonists of antiapoptotic proteins has grown. Beginning with a series of selective, potent BCL-XL antagonists containing an undesirable hydrazone functionali...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500030p
更新日期:2014-03-21 00:00:00
abstract::γ-Aminobutyric acid type A (GABAA) receptors are key mediators of central inhibitory neurotransmission and have been implicated in several disorders of the central nervous system. Some positive allosteric modulators (PAMs) of this receptor provide great therapeutic benefits to patients. However, adverse effects remain...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00340
更新日期:2020-09-15 00:00:00
abstract::Fluorescent biosensors constitute potent tools for probing biomolecules in their natural environment and for visualizing dynamic processes in complex biological samples, living cells, and organisms. They are well suited for highlighting molecular alterations associated with pathological disorders, thereby offering mea...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400472e
更新日期:2013-12-18 00:00:00
abstract::Several kalihinol natural products, members of the broader isocyanoterpene family of antimalarial agents, are potent inhibitors of Plasmodium falciparum, the agent of the most severe form of human malaria. Our previous total synthesis of kalihinol B provided a blueprint to generate many analogues within this family, s...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00013
更新日期:2017-02-16 00:00:00
abstract::In light of the biomedical significance of metallo-β-lactamases (MβLs), ten new mercaptoacetic acid thioester amino acid derivatives were synthesized and characterized. Biological activity assays indicated that all these synthesized compounds are very potent inhibitors of L1, exhibiting an IC50 value range of 0.018-2....
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00098
更新日期:2015-04-23 00:00:00
abstract::Replication Protein A is the primary eukaryotic ssDNA binding protein that has a central role in initiating the cellular response to DNA damage. RPA recruits multiple proteins to sites of DNA damage via the N-terminal domain of the 70 kDa subunit (RPA70N). Here we describe the optimization of a diphenylpyrazole carbox...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml5003629
更新日期:2014-11-11 00:00:00
abstract::[This corrects the article DOI: 10.1021/acsmedchemlett.8b00507.]. ...
journal_title:ACS medicinal chemistry letters
pub_type: 已发布勘误
doi:10.1021/acsmedchemlett.9b00316
更新日期:2019-08-06 00:00:00
abstract::Highly toxic bacterial ionophores are commonly used in veterinary medicine, but their therapeutic index is too narrow for human usage. With the goal of developing ionophores with a broader therapeutic index, we constructed highly derivatized synthetic ionophores. The toxicities of crown ether host-rotaxanes (CEHR's) a...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml3003204
更新日期:2013-01-10 00:00:00
abstract::Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved solubility at acidic pH and increased oral bioavailability in mo...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml900016y
更新日期:2010-01-12 00:00:00
abstract::In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular model...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.6b00027
更新日期:2016-03-12 00:00:00
abstract::Two novel benzofuran derivatives coupled with (99m)Tc complexes were tested as probes for imaging cerebral β-amyloid plaques using single photon emission tomography. Although both derivatives bound to Aβ(1-42) aggregates, (99m)Tc-BAT-BF showed higher affinity than (99m)Tc-MAMA-BF. In sections of brain tissue from an a...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100140d
更新日期:2010-08-02 00:00:00
abstract::We describe the synthesis and SAR studies of divin-a small molecule that blocks bacterial division by perturbing the assembly of proteins at the site of cell septation. The bacteriostatic mechanism of action of divin is distinct from other reported inhibitors of bacterial cell division and provides an opportunity for ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400234x
更新日期:2013-09-12 00:00:00
abstract::A novel series of quinazolinone T-type calcium channel antagonists have been prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 by modifications of the 3- and 4-positions of the quinazolinone ring afforded potent and selective antagonists that displayed in vivo central nervou...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100004r
更新日期:2010-02-01 00:00:00
abstract::[This corrects the article DOI: 10.1021/acsmedchemlett.9b00612.]. ...
journal_title:ACS medicinal chemistry letters
pub_type: 已发布勘误
doi:10.1021/acsmedchemlett.0c00336
更新日期:2020-06-24 00:00:00
abstract::We have developed a novel albumin-binding prodrug of doxorubicin that incorporates p-aminobenzyloxycarbonyl (PABC) as a 1,6 self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, as a substrate for the prostate-specific antigen (PSA) that is overexpressed in prostate carcinoma and represe...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100060m
更新日期:2010-05-26 00:00:00
abstract::With the COVID-19 pandemic, the evolutionary fate of SARS-CoV-2 becomes a matter of utmost concern. Mutation D614G in the spike (S) protein has become dominant, and recent evidence suggests it yields a more stable phenotype with higher transmission efficacy. We carry out a structural analysis that provides mechanistic...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00410
更新日期:2020-08-17 00:00:00
abstract::The ring closing metathesis/transannular etherification approach to the englerin nucleus was adapted to provide two key intermediates for analogue synthesis: the 4-desmethyl Δ5,6 tricycle and the 4-oxo Δ5,6 tricycle. The former was elaborated to 4-desmethyl englerin A and the latter served as a common precursor for en...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00161
更新日期:2017-06-06 00:00:00
abstract::The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chemistry (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series containing 2-substitute...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00462
更新日期:2020-10-13 00:00:00
abstract::Re(I) tricarbonyl polypyridine-based complexes are particularly attractive metal complexes in the field of inorganic chemical biology due to their luminescent properties, ease of conjugation to targeting biomolecules, and the possibility to prepare their "hot" (99m)Tc analogues for radioimaging. In this study, we prep...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500158w
更新日期:2014-05-15 00:00:00