Abstract：
:Proteins which bind methylated lysines ("readers" of the histone code) are important components in the epigenetic regulation of gene expression and can also modulate other proteins that contain methyl-lysine such as p53 and Rb. Recognition of methyl-lysine marks by MBT domains leads to compaction of chromatin and a repressed transcriptional state. Antagonists of MBT domains would serve as probes to interrogate the functional role of these proteins and initiate the chemical biology of methyl-lysine readers as a target class. Small-molecule MBT antagonists were designed based on the structure of histone peptide-MBT complexes and their interaction with MBT domains determined using a chemiluminescent assay and ITC. The ligands discovered antagonize native histone peptide binding, exhibiting 5-fold stronger binding affinity to L3MBTL1 than its preferred histone peptide. The first cocrystal structure of a small molecule bound to L3MBTL1 was determined and provides new insights into binding requirements for further ligand design.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Herold JM,Wigle TJ,Norris JL,Lam R,Korboukh VK,Gao C,Ingerman LA,Kireev DB,Senisterra G,Vedadi M,Tripathy A,Brown PJ,Arrowsmith CH,Jin J,Janzen WP,Frye SVdoi
10.1021/jm200045vsubject
Has Abstractpub_date
2011-04-14 00:00:00pages
2504-11issue
7eissn
0022-2623issn
1520-4804journal_volume
54pub_type
杂志文章abstract：:It is common practice to calculate large numbers of molecular descriptors, apply variable selection procedures to reduce the numbers, and then construct multiple linear regression (MLR) models with biological activity. The significance of these models is judged using the usual statistical tests. Unfortunately, these t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049111p
更新日期：2005-02-10 00:00:00
abstract：:The modulation of the endocannabinoid system is emerging as a viable avenue for the treatment of neurodegeneration, being involved in neuroprotective and anti-inflammatory processes. In particular, indirectly enhancing endocannabinoid signaling to therapeutic levels through FAAH inhibition might be beneficial for neur...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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更新日期：2016-07-14 00:00:00
abstract：:The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060435i
更新日期：2006-08-10 00:00:00
abstract：:The clinical use of anticancer lipids is severely limited by their ability to cause lysis of red blood cells prohibiting intravenous injection. Novel delivery systems are therefore required in order to develop anticancer ether lipids (AELs) into clinically useful anticancer drugs. In a recent article (J. Med. Chem. 20...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049006f
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abstract：:The understanding of the physiological role of the G-protein coupled serotonin 5-HT(7) receptor is largely rudimentary. Therefore, selective and potent pharmacological tools will add to the understanding of serotonergic effects mediated through this receptor. In this report, we describe two compound classes, chromans ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0498102
更新日期：2004-07-29 00:00:00
abstract：:Several imidazolylphenyl sulfamate and (imidazolylphenoxy)alkyl sulfamate derivatives were synthesized and evaluated as topically active carbonic anhydrase inhibitors. Water solubility, pKa, carbonic anhydrase inhibition, and partition coefficient for the compounds were measured. Sulfamic acid 2-[4-(1H-imidazol-1-yl)p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00104a003
更新日期：1992-12-25 00:00:00
abstract：:Targeting KRAS-PDEδ protein-protein interactions with small molecules represents a promising opportunity for developing novel antitumor agents. However, current KRAS-PDEδ inhibitors are limited by poor cellular antitumor potency and the druggability of the target remains to be validated by new inhibitors. To tackle th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00057
更新日期：2018-03-22 00:00:00
abstract：:A novel series of 3,4-dihydroxychalcones was synthesized to evaluate their effects against 5-lipoxygenase and cyclooxygenase. Almost all compounds exhibited potent inhibitory effects on 5-lipoxygenase with antioxidative effects, and some also inhibited cyclooxygenase. The 2',5'-disubstituted 3,4-dihydroxychalcones wit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00076a019
更新日期：1993-11-26 00:00:00
abstract：:We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure-activi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400645w
更新日期：2013-07-25 00:00:00
abstract：:Targeted protein degradation with bifunctional degraders is positioned as a remarkable game-changing strategy to control cellular protein levels and promises a new therapeutic modality in drug discovery. Light activation of a degrader to achieve exquisite spatiotemporal control over protein stability in cells has attr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01542
更新日期：2020-12-24 00:00:00
abstract：:The regulation of lipid metabolism and it's effect on glucose control and diabetes has received intense interest. Hormone-sensitive lipase (HSL) is a vital enzyme in lipid metabolism. A series of novel pyrrolopyrazinediones has been discovered that demonstrate submicromolar activity both in the enzyme assay and in a (...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020460y
更新日期：2003-03-27 00:00:00
abstract：:The use of deuteration in medicinal chemistry has exploded in the past years, and the FDA has recently approved the first deuterium-labeled drug. Precision deuteration goes beyond the pure and simple amelioration of the pharmacokinetic parameters of a drug and might provide an opportunity when facing problems in terms...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.8b01808
更新日期：2019-06-13 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801240d
更新日期：2009-03-12 00:00:00
abstract：:Androgen receptors are present in most advanced prostate cancer specimens, having a critical role in development of this type of cancer. For correct prognosis of patient conditions and treatment monitoring, noninvasive imaging techniques have great advantages over surgical procedures. We developed synthetic methodolog...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100289b
更新日期：2010-09-09 00:00:00
abstract：:Targeted imaging requires contrast agents that remain in the vasculature for extended periods of time. A new contrast agent is described in which gadolinium is encapsulated within an extremely stable carbon sphere, thus allowing for safe extended residence. Water solubility and small particle size is achieved with nov...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800521j
更新日期：2008-07-10 00:00:00
abstract：:The pharmaceutical industry has recognized that many drug-like molecules can self-aggregate in aqueous media and have physicochemical properties that skew experimental results and decisions. Herein, we introduce the use of a simple NMR strategy for detecting the formation of aggregates using dilution experiments that ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400535b
更新日期：2013-06-27 00:00:00
abstract：:In previous studies, we have grouped regions in space occupied by the vitamin D side chain into four: A, G, EA, and EG. We showed that the receptor (VDR) affinity of 1alpha,25-dihydroxyvitamin D3 derivatives increases, in terms of side-chain region, in the order EG, G, A, and EA. We called this the active space group ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970761l
更新日期：1998-04-23 00:00:00
abstract：:Evidence indicating that modifications at the 5- and 10-positions of classical folic acid antimetabolites lead to compounds with favorable differential membrane transport in tumor vs. normal proliferative tissue prompted an investigation of 5-alkyl-5-deaza analogues. 2-Amino-4-methyl-3,5-pyridinedicarbonitrile, prepar...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00156a029
更新日期：1986-06-01 00:00:00
abstract：:A one-pot synthesis of ageladine A and analogues is reported. The key Pictet-Spengler reaction between 2-aminohistamine and aryl aldehydes has been successfully utilized for the synthesis of the natural product and 14 analogues. These compounds were screened for their matrix metalloprotease (MMP) and kinase inhibition...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200039m
更新日期：2011-04-14 00:00:00
abstract：:High-resolution, three-dimensional structures of vancomycin and aglyco-vancomycin in DMSO were determined by nuclear magnetic resonance, metric matrix distance geometry, and molecular dynamics calculations. Conformational flexibility fast on the NMR time scale was examined by ensemble-based calculations which apply th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9705972
更新日期：1998-06-04 00:00:00
abstract：:A novel series of 16-substituted-4-azasteroids has been identified as potential tissue-selective androgen receptor modulators. These ligands display potent hAR binding and agonist activity, low virilizing potential, and good pharmacokinetic profiles in dogs. On the basis of its in vitro profile, 21 was evaluated in th...
journal_title：Journal of medicinal chemistry
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abstract：:Alpha-glucosidases play important roles in the digestion of carbohydrates and biosynthesis of viral envelope glycoproteins. Inhibitors of alpha-glucosidase are promising candidates for the development of antitype II diabetics and anti-AIDS drugs. Here, we report the synthesis and alpha-glucosidase inhibitory activity ...
journal_title：Journal of medicinal chemistry
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更新日期：2008-10-09 00:00:00
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journal_title：Journal of medicinal chemistry
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更新日期：2012-01-26 00:00:00
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journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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更新日期：1985-11-01 00:00:00
abstract：:Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11 and 16) exhibited potent cell growth inhibition in vitro (GI(50): 9 nM and 20 nM). Interestingly, both compounds displayed improved select...
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更新日期：2011-07-28 00:00:00
abstract：:Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01624
更新日期：2020-03-26 00:00:00
abstract：:N-Benzoyl-DL-phenylalanine (1) was found to possess hypoglycemic activity. A series of the analogues of compound 1 were prepared and evaluated for their blood glucose lowering activity. Both the steric effects of the phenylalanine moiety and the effects of variations in the acyl moiety were investigated. This study el...
journal_title：Journal of medicinal chemistry
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更新日期：2006-09-21 00:00:00
abstract：:A series of 1-(p-nitrophenyl)-2-aminoethanol derivatives and their morpholine analogues have been synthesized and pharmacologically investigated in order to confirm some pharmacological observations made with the N-isopropyl-substituted compounds. In agreement with the previously obtained results, the weak alpha-adren...
journal_title：Journal of medicinal chemistry
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更新日期：1979-06-01 00:00:00
abstract：:Coactivator-associated arginine methyltransferase 1 (CARM1) represents a valuable target for hormone-dependent tumors such as prostate and breast cancers. Here we report the enzyme and cellular characterization of the 1-benzyl-3,5-bis(3-bromo-4-hydroxybenzylidene)piperidin-4-one (7g) and its analogues 8a-l. Among them...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
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