Browse
Submit Data
Databases
API
Help

Dataset Information

23 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis and biological evaluation of 3-benzisoxazolyl-4-indolylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3?.

ABSTRACT: A series of novel 3-benzisoxazolyl-4-indolyl-maleimides were synthesized and evaluated for their GSK-3? inhibitory activity. Most compounds exhibited high inhibitory potency towards GSK-3?. Among them, compound 7j with an IC?? value of 0.73 nM was the most promising GSK-3? inhibitor. Preliminary structure-activity relationships were examined and showed that different substituents on the indole ring and N¹-position of the indole ring had varying degrees of influence on the GSK-3? inhibitory potency. Compounds 7c, 7f, 7j-l and 7o-q could obviously reduce A?-induced Tau hyperphosphorylation by inhibiting GSK-3? in a cell-based functional assay.

SUBMITTER: Ye Q

PROVIDER: S-EPMC6270165 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Synthesis and biological evaluation of 3-benzisoxazolyl-4-indolylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3β.

Ye Qing Q Li Meng M Zhou Yubo Y Pang Tao T Xu Lei L Cao Jiayi J Han Liang L Li Yujin Y Wang Weisi W Gao Jianrong J Li Jia J

Molecules (Basel, Switzerland) 20130513 5

A series of novel 3-benzisoxazolyl-4-indolyl-maleimides were synthesized and evaluated for their GSK-3β inhibitory activity. Most compounds exhibited high inhibitory potency towards GSK-3β. Among them, compound 7j with an IC₅₀ value of 0.73 nM was the most promising GSK-3β inhibitor. Preliminary structure-activity relationships were examined and showed that different substituents on the indole ring and N¹-position of the indole ring had varying degrees of influence on the GSK-3β inhibitory poten ...[more]

PMID: 23669633

Similar Datasets

Discovery of Selective, Substrate-Competitive, and Passive Membrane Permeable Glycogen Synthase Kinase-3? Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling of New C-Glycosylflavones.

Project description:Glycogen synthase kinase-3? (GSK-3?) is a key enzyme responsible for tau hyperphosphorylation and is a viable therapeutic target of Alzheimer's disease (AD). We developed a new class of GSK-3? inhibitors based on the 6- C-glycosylflavone isoorientin (1). The new inhibitors are passive membrane permeable and constitutively attenuate GSK-3? mediated tau hyperphosphorylation and amyloid neurotoxicity in an AD cellular model. Enzymatic assays and kinetic studies demonstrated that compound 30 is a GSK-3? substrate-competitive inhibitor with distinct kinase selectivity, isoform-selectivity and over 310-fold increased potency as compared to 1. Structure-activity relationship analyses and in silico modeling suggest the mechanism of actions by which the hydrophobic, ?-cation, and orthogonal multipolar interactions of 30 with the substrate site are critical for the GSK-3? inhibition and selectivity. The results provide new insights into GSK-3? drug discovery. The new inhibitors are valuable chemical probes and drug leads with therapeutic potential to tackle AD and other GSK-3? relevant diseases.

| S-EPMC7368552 | biostudies-literature

Design, Synthesis and Biological Evaluation of 7-Chloro-9H-pyrimido[4,5-b]indole-based Glycogen Synthase Kinase-3? Inhibitors.

Project description:Glycogen synthase kinase-3? (GSK-3?) represents a relevant drug target for the treatment of neurodegenerative pathologies including Alzheimer's disease. We herein report on the optimization of a novel class of GSK-3? inhibitors based on the tofacitinib-derived screen hit 3-((3R,4R)-3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (1). We synthesized a series of 19 novel 7-chloro-9H-pyrimido[4,5-b]indole-based derivatives and studied their structure-activity relationships with focus on the cyanoacetyl piperidine moiety. We unveiled the crucial role of the nitrile group and its importance for the activity of this compound series. A successful rigidization approach afforded 3-(3aRS,7aSR)-(1-(7-chloro-9H-pyrimido[4,5-b]indol-4-yl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)-propanenitrile (24), which displayed an IC50 value of 130 nM on GSK-3? and was further characterized by its metabolic stability. Finally, we disclosed the putative binding modes of the most potent inhibitors within the ATP binding site of GSK-3? by 1 µs molecular dynamics simulations.

| S-EPMC6630214 | biostudies-literature

The design and synthesis of potent and selective inhibitors of Trypanosoma brucei glycogen synthase kinase 3 for the treatment of human african trypanosomiasis.

Project description:Glycogen synthase kinase 3 (GSK3) is a genetically validated drug target for human African trypanosomiasis (HAT), also called African sleeping sickness. We report the synthesis and biological evaluation of aminopyrazole derivatives as Trypanosoma brucei GSK3 short inhibitors. Low nanomolar inhibitors, which had high selectivity over the off-target human CDK2 and good selectivity over human GSK3? enzyme, have been prepared. These potent kinase inhibitors demonstrated low micromolar levels of inhibition of the Trypanosoma brucei brucei parasite grown in culture.

| S-EPMC4175002 | biostudies-literature

Kinome chemoproteomics characterization of pyrrolo[3,4-c]pyrazoles as potent and selective inhibitors of glycogen synthase kinase 3.

Project description:Glycogen synthase kinase 3 has evolutionarily conserved roles in cell signaling and metabolism and is a recognized drug target in neurological pathologies, most prominently bipolar disorder. More recently it has been suggested that GSK3 may be a target for the treatment of trypanosomatid parasite infections, e.g. with T. brucei, due to the lethal phenotype observed in parasite GSK3 short RNAi knockdown experiments. Here we investigated the kinome selectivity of a library of pyrrolo[3,4-c]pyrazol inhibitors that were developed against T. brucei GSK3 but that also interact with the human orthologue and other protein kinases. We applied label-free MS-based kinome chemoproteomics profiling with kinobeads to obtain the selectivity profiles of all 39 library members against 217 human protein and lipid kinases. This allowed us to study the structure-activity relationship of the library members as well as the chemical genetic relationships between kinase targets. As a result, we identified a novel and highly selective HsGSK3 inhibitor containing a 2-chloroaniline-substituted squaric acid amide pharmacophore that confers low nanomolar (IC50 = 2.8 nM) and sub-micromolar potency against purified and cellular HsGSK3. The inhibitor will be useful as a new lead for GSK3 inhibitor development and as a chemical genetic probe to study roles of GSK3 in cell signaling.

| S-EPMC5939582 | biostudies-literature

Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors.

Project description:G protein-coupled receptors (GPCRs) are central to many physiological processes. Regulation of this superfamily of receptors is controlled by GPCR kinases (GRKs), some of which have been implicated in heart failure. GSK180736A, developed as a Rho-associated coiled-coil kinase 1 (ROCK1) inhibitor, was identified as an inhibitor of GRK2 and co-crystallized in the active site. Guided by its binding pose overlaid with the binding pose of a known potent GRK2 inhibitor, Takeda103A, a library of hybrid inhibitors was developed. This campaign produced several compounds possessing high potency and selectivity for GRK2 over other GRK subfamilies, PKA, and ROCK1. The most selective compound, 12n (CCG-224406), had an IC50 for GRK2 of 130 nM, >700-fold selectivity over other GRK subfamilies, and no detectable inhibition of ROCK1. Four of the new inhibitors were crystallized with GRK2 to give molecular insights into the binding and kinase selectivity of this class of inhibitors.

| S-EPMC4890168 | biostudies-literature

Synthesis and biological evaluation of indole-based UC-112 analogs as potent and selective survivin inhibitors.

Project description:The anti-apoptotic protein survivin is highly expressed in cancer cells but has a very low expression in fully differentiated adult cells. Overexpression of survivin is positively correlated with cancer cell resistance to chemotherapy and radiotherapy, cancer cell metastasis, and poor patient prognosis. Therefore, selective targeting survivin represents an attractive strategy for the development of anticancer therapeutics. Herein, we reported the extensive structural modification of our recently discovered selective survivin inhibitor UC-112 and the synthesis of thirty-three new analogs. The structure-activity relationship (SAR) study indicated that replacement of the benzyloxy moeity in UC-112 with an indole moiety was preferred to other moieties. Among these UC-112 analogs, 10f, 10h, 10k, 10n showed the most potent antiproliferative activities. Interestingly, they were more potent against the P-glycoprotein overexpressing cancer cell lines compared with the parental cancer cell lines. Mechanistic studies confirmed that new analogs maintained their unique selectivity against survivin among the IAP family members. In vivo study using 10f in a human A375 melanoma xenograft model revealed that it effectively inhibited melanoma tumor growth without observable acute toxicity. Collectively, this study strongly supports the further preclinical development of selective survivin inhibitors based on the UC-112 scaffold.

| S-EPMC5849576 | biostudies-literature

Glycogen synthase kinase-3 inhibitors as potent therapeutic agents for the treatment of Parkinson disease.

Project description:Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. Because the current therapies only lead to temporary, limited improvement and have severe side effects, new approaches to treat PD need to be developed. To discover new targets for potential therapeutic intervention, a chemical genetic approach involving the use of small molecules as pharmacological tools has been implemented. First, a screening of an in-house chemical library on a well-established cellular model of PD was done followed by a detailed pharmacological analysis of the hits. Here, we report the results found for the small heterocyclic derivative called SC001, which after different enzymatic assays was revealed to be a new glycogen synthase kinase-3 (GSK-3) inhibitor with IC(50) = 3.38 ± 0.08 ?M. To confirm that GSK-3 could be a good target for PD, the evaluation of a set of structurally diverse GSK-3 inhibitors as neuroprotective agents for PD was performed. Results show that inhibitors of GSK-3 have neuroprotective effects in vitro representing a new pharmacological option for the disease-modifying treatment of PD. Furthermore, we show that SC001 is able to cross the blood-brain barrier, protects dopaminergic neurons, and reduces microglia activation in in vivo models of Parkinson disease, being a good candidate for further drug development.

| S-EPMC3582296 | biostudies-literature

Synthesis and Biological Evaluation of Pyrazolo[1,5-a]pyrimidine Compounds as Potent and Selective Pim-1 Inhibitors.

Project description:Pim-1 has emerged as an attractive target for developing therapeutic agents for treating disorders involving abnormal cell growth, especially cancers. Herein we present lead optimization, chemical synthesis and biological evaluation of pyrazolo[1,5-a]pyrimidine compounds as potent and selective inhibitors of Pim-1 starting from a hit from virtual screening. These pyrazolo[1,5-a]pyrimidine compounds strongly inhibited Pim-1 and Flt-3 kinases. Selected compounds suppressed both the phosphorylation of BAD protein in a cell-based assay and 2-dimensional colony formation in a clonogenic cell survival assay at submicromolar potency, suggesting that cellular activity was mediated through inhibition of Pim-1. Moreover, these Pim-1 inhibitors did not show significant hERG inhibition at 30 ?M concentration. The lead compound proved to be highly selective against a panel of 119 oncogenic kinases, indicating it had an improved safety profile compared with the first generation Pim-1 inhibitor SGI-1776.

| S-EPMC4291737 | biostudies-literature

Evaluation of Improved Glycogen Synthase Kinase-3? Inhibitors in Models of Acute Myeloid Leukemia.

Project description:The challenge for glycogen synthase kinase-3 (GSK-3) inhibitor design lies in achieving high selectivity for one isoform over the other. The therapy of certain diseases, such as acute myeloid leukemia (AML), may require ?-isoform specific targeting. The scorpion shaped GSK-3 inhibitors developed by our group achieved the highest GSK-3? selectivity reported so far but suffered from insufficient aqueous solubility. This work presents the solubility-driven optimization of our isoform-selective inhibitors using a scorpion shaped lead. Among 15 novel compounds, compound 27 showed high activity against GSK-3?/? with the highest GSK-3? selectivity reported to date. Compound 27 was profiled for bioavailability and toxicity in a zebrafish embryo phenotype assay. Selective GSK-3? targeting in AML cell lines was achieved with compound 27, resulting in a strong differentiation phenotype and colony formation impairment, confirming the potential of GSK-3? inhibition in AML therapy.

| S-EPMC4883112 | biostudies-literature

Selective Acetamidine-Based Nitric Oxide Synthase Inhibitors: Synthesis, Docking, and Biological Studies.

Project description:N-[(3-Aminomethyl)benzyl]acetamidine derivatives were synthesized and in vitro evaluated as inhibitors of the inducible isoform of nitric oxide synthase (iNOS). Because of the high potency of action and the excellent selectivity over the endothelial nitric oxide synthase (eNOS), compound 10 was ex vivo evaluated on isolated and perfused resistance arteries. The results confirm that compound 10 selectively inhibits the iNOS, without affecting the endothelial isoform. The outcome of the docking studies showed that the hydrophobic interaction is the driving force of the binding process, especially for iNOS, where the binding pocket is characterized by a significant lipophilic region.

| S-EPMC4468396 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data