Browse
Submit Data
Databases
API
Help

Dataset Information

11 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Development of organometallic S6K1 inhibitors.

ABSTRACT: Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previously used to target other kinases. Biochemical data demonstrate that EM5 and FL772 inhibit the kinase with IC50 value in the low nanomolar range at 100 μM ATP and that the more potent FL772 compound has a greater than 100-fold specificity over S6K2. The crystal structures of S6K1 bound to staurosporine, EM5, and FL772 reveal that the EM5 and FL772 inhibitors bind in the ATP binding pocket and make S6K1-specific contacts, resulting in changes to the p-loop, αC helix, and αD helix when compared to the staurosporine-bound structure. Cellular data reveal that FL772 is able to inhibit S6K phosphorylation in yeast cells. Together, these studies demonstrate that potent, selective, and cell permeable S6K1 inhibitors can be prepared and provide a scaffold for future development of S6K inhibitors with possible therapeutic applications.

SUBMITTER: Qin J

PROVIDER: S-EPMC4289024 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Organometallic Pyridylnaphthalimide Complexes as Protein Kinase Inhibitors.

Project description:A new metal-containing scaffold for the design of protein kinase inhibitors is introduced. Key feature is a 3-(2-pyridyl)-1,8-naphthalimide "pharmacophore chelate ligand" which is designed to form two hydrogen bonds with the hinge region of the ATP-binding site and is at the same time capable of serving as a stable bidentate ligand through C-H-activation at the 4-position of the electron-deficient naphthalene moiety. This C-H-activation leads to a reduced demand for coordinating heteroatoms and thus sets the basis for a very efficient three-step synthesis starting from 1,8-naphthalic anhydride. The versatility of this ligand is demonstrated with the discovery of a ruthenium complex that functions as a nanomolar inhibitor for myosin light-chain kinase (MYLK or MLCK).

| S-EPMC3170819 | biostudies-literature

Crystal structures of the S6K1 kinase domain in complexes with inhibitors.

Project description:Ribosomal protein S6 kinase 1 (S6K1) is a serine/threonine protein kinase that plays an important role in the PIK3/mTOR signaling pathway, and is implicated in diseases including diabetes, obesity, and cancer. The crystal structures of the S6K1 kinase domain in complexes with staurosporine and the S6K1-specific inhibitor PF-4708671 have been reported. In the present study, five compounds (F108, F109, F176, F177, and F179) were newly identified by in silico screening of a chemical library and kinase assay. The crystal structures of the five inhibitors in complexes with the S6K1 kinase domain were determined at resolutions between 1.85 and 2.10 Å. All of the inhibitors bound to the ATP binding site, lying along the P-loop, while the activation loop stayed in the inactive form. Compound F179, with a carbonyl group in the middle of the molecule, altered the αC helix conformation by interacting with the invariant Lys123. Compounds F176 and F177 bound slightly distant from the hinge region, and their sulfoamide groups formed polar interactions with the protein. The structural features required for the specific binding of inhibitors are discussed.

| S-EPMC4125821 | biostudies-literature

Computer-aided discovery of phenylpyrazole based amides as potent S6K1 inhibitors.

Project description:Ribosomal protein S6 kinase beta-1 (S6K1) is an attractive therapeutic target. In this study, computational analysis of five thiophene urea-based S6K1 inhibitors was performed. Molecular docking showed that the five compounds formed hydrogen bonds with residues Glu173 and Leu175 of S6K1 and hydrophobic interactions with residues Val105, Leu97 and Met225, and these interactions were key elements for the inhibitory potency of the compounds. Binding free energy (ΔG bind) decomposition analysis showed that Leu97, Glu173, Val 105, Leu175, Leu97 and Met225 contribute the most to ΔG bind. Based on the computer results, phenylpyrazole based amides (D1-D3) were designed and synthesized. Biological evaluation revealed that D2 exhibited 15.9 nM S6K1 inhibition, medium microsomal stability and desirable bioavailability.

| S-EPMC7605259 | biostudies-literature

Small molecule H89 renders the phosphorylation of S6K1 and AKT resistant to mTOR inhibitors.

Project description:The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr kinase that comprises two complexes, termed mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 phosphorylates S6K1 at Thr 389, whereas mTORC2 phosphorylates AKT at Ser 473 to promote cell growth. As the mTOR name implies it is the target of natural product called rapamycin, a clinically approved drug used to treat human disease. Short-term rapamycin treatment inhibits the kinase activity of mTORC1 but not mTORC2. However, the ATP-competitive catalytic mTOR inhibitor Torin1 was identified to inhibit the kinase activity of both mTORC1 and mTORC2. Here, we report that H89 (N-(2-(4-bromocinnamylamino) ethyl)-5-isoquinolinesulfonamide), a well-characterized ATP-mimetic kinase inhibitor, renders the phosphorylation of S6K1 and AKT resistant to mTOR inhibitors across multiple cell lines. Moreover, H89 prevented the dephosphorylation of AKT and S6K1 under nutrient depleted conditions. PKA and other known H89-targeted kinases do not alter the phosphorylation status of S6K1 and AKT. Pharmacological inhibition of some phosphatases also enhanced S6K1 and AKT phosphorylation. These findings suggest a new target for H89 by which it sustains the phosphorylation status of S6K1 and AKT, resulting in mTOR signaling.

| S-EPMC7261416 | biostudies-literature

Biological evaluation of novel thiomaltol-based organometallic complexes as topoisomerase IIα inhibitors.

Project description:Topoisomerase IIα (topo2α) is an essential nuclear enzyme involved in DNA replication, transcription, recombination, chromosome condensation, and highly expressed in many tumors. Thus, topo2α-targeting has become a very efficient and well-established anticancer strategy. Herein, we investigate the cytotoxic and DNA-damaging activity of thiomaltol-containing ruthenium-, osmium-, rhodium- and iridium-based organometallic complexes in human mammary carcinoma cell lines by means of several biological assays, including knockdown of topo2α expression levels by RNA interference. Results suggest that inhibition of topo2α is a key process in the cytotoxic mechanism for some of the compounds, whereas direct induction of DNA double-strand breaks or other DNA damage is mostly rather minor. In addition, molecular modeling studies performed for two of the compounds (with Ru(II) as the metal center) evinces that these complexes are able to access the DNA-binding pocket of the enzyme, where the hydrophilic environment favors the interaction with highly polar complexes. These findings substantiate the potential of these compounds for application as antitumor metallopharmaceuticals.

| S-EPMC7186247 | biostudies-literature

Organometallic small molecule kinase inhibitors - direct incorporation of Re and 99mTc into Opaganib®.

Project description:[(η5-Cp)ReI(CO)3] was incorporated into the kinase inhibitor Opaganib®. The resulting bioorganometallic complex showed a similar anti-cancer activity to Opaganib® against PC-3 cancer cells. The IC50 value for the kinase SK2 is 30x higher than that of Opaganib®. The 99mTc homologue was synthesized, completing a matched-pair for molecular theranostics.

| S-EPMC8658909 | biostudies-literature

Development of Ferromagnetic Materials Containing Co2P, Fe2P Phases from Organometallic Dendrimers Precursors.

Project description:The development of synthesis methods to access advanced materials, such as magnetic materials that combine multimetallic phosphide phases, remains a worthy research challenge. The most widely used strategies for the synthesis of magnetic transition metal phosphides (TMPs) are organometallic approaches. In this study, Fe-containing homometallic dendrimers and Fe/Co-containing heterometallic dendrimers were used to synthesize magnetic materials containing multimetallic phosphide phases. The crystalline nature of the nearly aggregated particles was indicated for both designed magnetic samples. In contrast to heterometallic samples, homometallic samples showed dendritic effects on their magnetic properties. Specifically, saturation magnetization (Ms) and coercivity (Hc) decrease as dendritic generation increases. Incorporating cobalt into the homometallic dendrimers to prepare the heterometallic dendrimers markedly increases the magnetic properties of the magnetic materials from 60 to 75 emu/g. Ferromagnetism in homometallic and heterometallic particles shows different responses to temperature changes. For example, heterometallic samples were less sensitive to temperature changes due to the presence of Co2P in contrast to the homometallic ones, which show an abrupt change in their slopes at a temperature close to 209 K, which appears to be related to the Fe2P ratios. This study presents dendrimers as a new type of precursor for the assembly of magnetic materials containing a mixture of iron- and cobalt-phosphides phases with tunable magnetism, and provides an opportunity to understand magnetism in such materials.

| S-EPMC8588225 | biostudies-literature

Combination of pharmacophore hypothesis, genetic function approximation model, and molecular docking to identify novel inhibitors of S6K1.

Project description:S6K1 has emerged as a potential target for the treatment for obesity, type II diabetes and cancer diseases. Discovery of S6K1 inhibitors has thus attracted much attention in recent years. In this investigation, a hybrid virtual screening method that involves pharmacophore hypothesis, genetic function approximation (GFA) model, and molecular docking technology has been used to discover S6K1 inhibitors especially with novel scaffolds. The common feature pharmacophore hypothesis and GFA regression model of S6K1 inhibitors were first developed and applied in a virtual screen of the Specs database for retrieving S6K1 inhibitors. Then, the molecular docking method was carried out to re-filter these screened compounds. Finally, 60 compounds with promising S6K1 inhibitory activity were carefully selected and have been handed over to the other group to complete the follow-up compound synthesis (or purchase) and activity test.

| S-EPMC3824193 | biostudies-literature

Ferrocenyl 2,5-Piperazinediones as Tubulin-Binding Organometallic ABCB1 and ABCG2 Inhibitors Active against MDR Cells.

Project description:The tubulin-microtubule system is a common target of many anticancer drugs. However, the use of chemotherapeutics frequently leads to the development of a clinically relevant phenomenon of multidrug resistance (MDR). One of the basic mechanisms involved in MDR involves elevated expression and/or activity of several ATP-binding cassette superfamily members (ABC transporters) which are normally responsible for the efflux of xenobiotics or secondary metabolites outside the cell. Here we present the synthesis and biological characteristics of ferrocenyl analogues of plinabulin, i.e. one of the so-called "spindle poisons". We found that replacement of the phenyl group of plinabulin by the ferrocenyl moiety turns this compound into a potent inhibitor of ABCB1 and ABCG2, thus making it possible to overcome the multidrug resistance phenomenon. We also demonstrated that the alkyl group attached to the imidazole moiety of ferrocenyl analogues of plinabulin strongly affects their potency to inhibit tubulin polymerization.

| S-EPMC4904264 | biostudies-literature

Catalytic organometallic anticancer complexes.

Project description:Organometallic complexes offer chemistry that is not accessible to purely organic molecules and, hence, potentially new mechanisms of drug action. We show here that the presence of both an iodido ligand and a sigma-donor/pi-acceptor phenylazopyridine ligand confers remarkable inertness toward ligand substitution on the half-sandwich "piano-stool" ruthenium arene complexes [(eta(6)-arene)Ru(azpy)I](+) (where arene = p-cymene or biphenyl, and azpy = N,N-dimethylphenyl- or hydroxyphenyl-azopyridine) in aqueous solution. Surprisingly, despite this inertness, these complexes are highly cytotoxic to human ovarian A2780 and human lung A549 cancer cells. Fluorescence-trapping experiments in A549 cells suggest that the cytotoxicity arises from an increase in reactive oxygen species. Redox activity of these azopyridine Ru(II) complexes was confirmed by electrochemical measurements. The first one-electron reduction step (half-wave potential -0.2 to -0.4 V) is assignable to reduction of the azo group of the ligand. In contrast, the unbound azopyridine ligands are not readily reduced. Intriguingly the ruthenium complex acted as a catalyst in reactions with the tripeptide glutathione (gamma-L-Glu-L-Cys-Gly), a strong reducing agent present in cells at millimolar concentrations; millimolar amounts of glutathione were oxidized to glutathione disulfide in the presence of micromolar ruthenium concentrations. A redox cycle involving glutathione attack on the azo bond of coordinated azopyridine is proposed. Such ligand-based redox reactions provide new concepts for the design of catalytic drugs.

| S-EPMC2503924 | biostudies-literature

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