Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The Guareschi Pyridine Scaffold as a Valuable Platform for the Identification of Selective PI3K Inhibitors.

ABSTRACT: A novel series of 4-aryl-3-cyano-2-(3-hydroxyphenyl)-6-morpholino-pyridines have been designed as potential phosphatidylinositol-3-kinase (PI3K) inhibitors. The compounds have been synthesized using the Guareschi reaction to prepare the key 4-aryl-3-cyano-2,6-dihydroxypyridine intermediate. A different selectivity according to the nature of the aryl group has been observed. Compound 9b is a selective inhibitor against the PI3K? isoform, maintaining a good inhibitory activity. Docking studies were also performed in order to rationalize its profile of selectivity.

SUBMITTER: Galli U

PROVIDER: S-EPMC6332036 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

The Guareschi Pyridine Scaffold as a Valuable Platform for the Identification of Selective PI3K Inhibitors.

Galli Ubaldina U Ciraolo Elisa E Massarotti Alberto A Margaria Jean Piero JP Sorba Giovanni G Hirsch Emilio E Tron Gian Cesare GC

Molecules (Basel, Switzerland) 20150918 9

A novel series of 4-aryl-3-cyano-2-(3-hydroxyphenyl)-6-morpholino-pyridines have been designed as potential phosphatidylinositol-3-kinase (PI3K) inhibitors. The compounds have been synthesized using the Guareschi reaction to prepare the key 4-aryl-3-cyano-2,6-dihydroxypyridine intermediate. A different selectivity according to the nature of the aryl group has been observed. Compound 9b is a selective inhibitor against the PI3Kα isoform, maintaining a good inhibitory activity. Docking studies wer ...[more]

PMID: 26393561

Similar Datasets

Exploring <i>N</i>-Arylsulfonyl-l-proline Scaffold as a Platform for Potent and Selective αvβ1 Integrin Inhibitors.

Project description:One small molecule inhibitor of αvβ1 integrin, c8, shows antifibrotic effects in multiple in vivo mouse models. Here we synthesized c8 analogues and systematically investigate their structure-activity relationships (SAR) in αvβ1 integrin inhibition. N-Phenylsulfonyl-l-homoproline analogues of c8 maintained excellent potency against αvβ1 integrin while retaining good selectivity over other RGD integrins. In addition, 2-aminopyridine or cyclic guanidine analogues were shown to be equally potent to c8. A rigid phenyl linker increased the potency compared to c8, but the selectivity over other RGD integrins diminished. These results can provide further insights on design of αvβ1 integrin inhibitors as antifibrotics.

| S-EPMC5066160 | biostudies-literature

An efficient and versatile synthesis of GlcNAcstatins-potent and selective O-GlcNAcase inhibitors built on the tetrahydroimidazo[1,2-a]pyridine scaffold.

Project description:We report a novel approach to the synthesis of GlcNAcstatins-members of an emerging family of potent and selective inhibitors of peptidyl O-GlcNAc hydrolase build upon tetrahydroimidazo[1,2-a]pyridine scaffold. Making use of a streamlined synthetic sequence featuring de novo synthesis of imidazoles from glyoxal, ammonia and aldehydes, a properly functionalised linear GlcNAcstatin precursor has been efficiently prepared starting from methyl 3,4-O-(2',3'-dimethoxybutane-2',3'-diyl)-?-d-mannopyranoside. Subsequent ring closure of the linear precursor in an intramolecular S(N)2 process furnished the key fused d-mannose-imidazole GlcNAcstatin precursor in excellent yield. Finally, a sequence of transformations of this key intermediate granted expeditious access to a variety of the target compounds bearing a C(2)-phenethyl group and a range of N(8) acyl substituents. The versatility of the new approach stems from an appropriate choice of a set of acid labile permanent protecting groups on the monosaccharide starting material. Application was demonstrated by the synthesis of GlcNAcstatins containing polyunsaturated and thiol-containing amido substituents.

| S-EPMC2956484 | biostudies-literature

PI3K isoform-selective inhibitors: next-generation targeted cancer therapies.

Project description:The pivotal roles of phosphatidylinositol 3-kinases (PI3Ks) in human cancers have inspired active development of small molecules to inhibit these lipid kinases. However, the first-generation pan-PI3K and dual-PI3K/mTOR inhibitors have encountered problems in clinical trials, with limited efficacies as a monotherapeutic agent as well as a relatively high rate of side effects. It is increasingly recognized that different PI3K isoforms play non-redundant roles in particular tumor types, which has prompted the development of isoform-selective inhibitors for pre-selected patients with the aim for improving efficacy while decreasing undesirable side effects. The success of PI3K isoform-selective inhibitors is represented by CAL101 (Idelalisib), a first-in-class PI3Kδ-selective small-molecule inhibitor that has been approved by the FDA for the treatment of chronic lymphocytic leukemia, indolent B-cell non-Hodgkin's lymphoma and relapsed small lymphocytic lymphoma. Inhibitors targeting other PI3K isoforms are also being extensively developed. This review focuses on the recent progress in development of PI3K isoform-selective inhibitors for cancer therapy. A deeper understanding of the action modes of novel PI3K isoform-selective inhibitors will provide valuable information to further validate the concept of targeting specific PI3K isoforms, while the identification of biomarkers to stratify patients who are likely to benefit from the therapy will be essential for the success of these agents.

| S-EPMC4648175 | biostudies-other

Identification of Selective CYP3A7 and CYP3A4 Substrates and Inhibitors Using a High-Throughput Screening Platform.

Project description:Cytochrome P450 (CYP) 3A7 is one of the major xenobiotic metabolizing enzymes in human embryonic, fetal, and newborn liver. CYP3A7 expression has also been observed in a subset of the adult population, including pregnant women, as well as in various cancer patients. The characterization of CYP3A7 is not as extensive as other CYPs, and health authorities have yet to provide guidance towards DDI assessment. To identify potential CYP3A7-specific molecules, we used a P450-Glo CYP3A7 enzyme assay to screen a library of ∼5,000 compounds, including FDA-approved drugs and drug-like molecules, and compared these screening data with that from a P450-Glo CYP3A4 assay. Additionally, a subset of 1,000 randomly selected compounds were tested in a metabolic stability assay. By combining the data from the qHTS P450-Glo and metabolic stability assays, we identified several chemical features important for CYP3A7 selectivity. Halometasone was chosen for further evaluation as a potential CYP3A7-selective inhibitor using molecular docking. From the metabolic stability assay, we identified twenty-two CYP3A7-selective substrates over CYP3A4 in supersome setting. Our data shows that CYP3A7 has ligand promiscuity, much like CYP3A4. Furthermore, we have established a large, high-quality dataset that can be used in predictive modeling for future drug metabolism and interaction studies.

| S-EPMC9283723 | biostudies-literature

Identification of Novel PI3K? Selective Inhibitors by SVM-Based Multistage Virtual Screening and Molecular Dynamics Simulations.

Project description:Phosphoinositide 3 kinase delta (PI3K?) is a lipid kinase that has been implicated in a variety of immune mediated disorders. The research on isoform selectivity was crucial for reducing side effects. In the current study, an optimized hierarchical multistage virtual screening method was utilized for screening the PI3K? selective inhibitors. The method sequentially applied a support vector machine (SVM), a protein ligand interaction fingerprint (PLIF) pharmacophore, and a molecular docking approach. The evaluation of the validation set showed a high hit rate and a high enrichment factor of 75.1% and 301.66, respectively. This multistage virtual screening method was then utilized to screen the NCI database. From the final hit list, Compound 10 has great potential as the PI3K? inhibitor with micromolar inhibition in the PI3K? kinase activity assay. This compound also shows selectivity against PI3K? kinase. The method combining SVM, pharmacophore, and docking was capable of screening out the compounds with potential PI3K? selective inhibitors. Moreover, structural modification of Compound 10 will contribute to investigating the novel scaffold and designing novel PI3K? inhibitors.

| S-EPMC6928688 | biostudies-literature

Scaffold hopping approach on the route to selective tankyrase inhibitors.

Project description:A virtual screening procedure was applied to identify new tankyrase inhibitors. Through pharmacophore screening of a compounds collection from the SPECS database, the methoxy[l]benzothieno[2,3-c]quinolin-6(5H)-one scaffold was identified as nicotinamide mimetic able to inhibit tankyrase activity at low micromolar concentration. In order to improve potency and selectivity, tandem structure-based and scaffold hopping approaches were carried out over the new scaffold leading to the discovery of the 2-(phenyl)-3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-one as powerful chemotype suitable for tankyrase inhibition. The best compound 2-(4-tert-butyl-phenyl)-3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-one (23) displayed nanomolar potencies (IC50s TNKS-1 = 21 nM and TNKS-2 = 29 nM) and high selectivity when profiled against several other PARPs. Furthermore, a striking Wnt signaling, as well as cell growth inhibition, was observed assaying 23 in DLD-1 cancer cells.

| S-EPMC4415586 | biostudies-literature

PI3K?-selective and PI3K?/?-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma.

Project description:INTRODUCTION:The efficacy of the prototypical phosphatidylinositol-3-kinase (PI3K) inhibitor idelalisib for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) has led to development of multiple compounds targeting this pathway. Areas Covered: We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of B cell receptor signaling, blockade of microenvironmental pro-survival signals, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110? in regulatory T cells). We evaluate PI3K inhibitors that have entered trials for the treatment of lymphoma, focusing on agents with selectivity for PI3K? and PI3K?. Expert Opinion: PI3K inhibitors, particularly those that target p110?, have robust efficacy in the treatment of CLL and iNHL. However, idelalisib has infectious and autoimmune toxicities that limit its use. Outside of trials, idelalisib should be restricted to CLL patients with progression on ibrutinib or iNHL patients with progression on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.

| S-EPMC5747968 | biostudies-literature

Design of Selective Benzoxazepin PI3K? Inhibitors Through Control of Dihedral Angles.

Project description:A novel selective benzoxazepin inhibitor of PI3K? has been discovered. Beginning from compound 3, an ?PI3K inhibitor, we utilized structure-based drug design and computational analysis of dihedral torsion angles to optimize for PI3K? isoform potency and isoform selectivity. Further medicinal chemistry optimization of the series led to the identification of 24, a highly potent and selective inhibitor of PI3K?.

| S-EPMC5601369 | biostudies-literature

Identification and Characterizations of Novel, Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search.

Project description:SET7, serving as the only histone methyltransferase that monomethylates 'Lys-4' of histone H3, has been proved to function as a key regulator in diverse biological processes, such as cell proliferation, transcriptional network regulation in embryonic stem cell, cell cycle control, protein stability, heart morphogenesis and development. What's more, SET7 is involved inthe pathogenesis of alopecia aerate, breast cancer, tumor and cancer progression, atherosclerosis in human carotid plaques, chronic renal diseases, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis. Therefore, there is urgent need to develop novel SET7 inhibitors. In this paper, based on DC-S239 which has been previously reported in our group, we employed scaffold hopping- and 2D fingerprint-based similarity searches and identified DC-S285 as the new hit compound targeting SET7 (IC50 = 9.3 μM). Both radioactive tracing and NMR experiments validated the interactions between DC-S285 and SET7 followed by the second-round similarity search leading to the identification ofDC-S303 with the IC50 value of 1.1 μM. In cellular level, DC-S285 retarded tumor cell proliferation and showed selectivity against MCF7 (IC50 = 21.4 μM), Jurkat (IC50 = 2.2 μM), THP1 (IC50 = 3.5 μM), U937 (IC50 = 3.9 μM) cell lines. Docking calculations suggested that DC-S303 share similar binding mode with the parent compoundDC-S239. What's more, it presented good selectivity against other epigenetic targets, including SETD1B, SETD8, G9a, SMYD2 and EZH2. DC-S303 can serve as a drug-like scaffold which may need further optimization for drug development, and can be used as chemical probe to help the community to better understand the SET7 biology.

| S-EPMC6017732 | biostudies-literature

Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors.

Project description:Inhibition of the lipid kinase PI3K? 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 PI3K? isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3K? inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.

| S-EPMC4983741 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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