Month: October 2022

Bhakuni, Rashmi; Shaik, Althaf; Priya, Bhanu; Kirubakaran, Sivapriya published the artcile< Characterization of SPK 98, a Torin2 analog, as ATR and mTOR dual kinase inhibitor>, SDS of cas: 1223001-51-1, the main research area is Torin2 analog ATR mTOR dual kinase inhibitor; ATM; ATR; Cell cycle arrest; DNA damage response; Premature chromatin condensation.

A series of Torin2, a second-generation ATP-competitive inhibitor, analogs were biol. characterized to identify their potential for ATR and mTOR kinase inhibition. Compound SPK 98 was observed to inhibit ATR/mTOR kinase selectively over ATM kinase in HCT 116 cell line. In addition to that, SPK 98 on 30 min incubation with human, mice and rat liver microsomes showed improved properties with an increased half-life (a maximum T 1/2 of 157 min) and internal clearance in mouse as compared to Torin2. Further, SPK 98 was also noticed to indulge in inducing premature chromatin condensation as a result of ATR/mTOR kinase inhibition at 50 nM. In a nutshell, our work presents the identification and characterization of SPK 98, a small mol. inhibitor, which exhibits improved specific inhibition for ATR at a lower concentration than Torin2.

Bioorganic & Medicinal Chemistry Letters published new progress about Antitumor agents (potential as). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, SDS of cas: 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Gruber, Franz S.; Johnston, Zoe C.; Norcross, Neil R.; Georgiou, Irene; Wilson, Caroline; Read, Kevin D.; Gilbert, Ian H.; Swedlow, Jason R.; da Silva, Sarah Martins; Barratt, Christopher L. R. published the artcile< Compounds enhancing human sperm motility identified using a high-throughput phenotypic screening platform>, Electric Literature of 1223001-51-1, the main research area is human sperm motility semen high throughput phenotypic phosphodiesterase inhibitor; drug discovery; high-throughput screening; sperm motility; spermatozoa; subfertility.

Can a high-throughput screening (HTS) platform facilitate male fertility drug discovery. An HTS platform identified a large number of compounds that enhanced sperm motility. Several efforts to find small mols. modulating sperm function have been performed but none have used high-throughput technol. Healthy donor semen samples were used and samples were pooled (3-5 donors per pool). Primary screening was performed singly; dose-response screening was performed in duplicate (using independent donor pools). Spermatozoa isolated from healthy donors were prepared by d. gradient centrifugation and incubated in 384-well plates with compounds (6.25 μM) to identify those compounds with enhancing effects on motility. Approx. 17 000 compounds from the libraries, ReFRAME, Prestwick, Tocris, LOPAC, CLOUD and MMV Pathogen Box, were screened. Dose-response experiments of screening hits were performed to confirm the enhancing effect on sperm motility. Experiments were performed in a university setting. From our primary single concentration screening, 105 compounds elicited an enhancing effect on sperm motility compared to dimethylsulfoxide-treated wells. Confirmed enhancing compounds were grouped based on their annotated targets/target classes. A major target class, phosphodiesterase inhibitors, were identified, in particular PDE10A inhibitors as well as number of compounds not previously known to enhance human sperm motility, such as those related to GABA signalling. Although this approach provides data about the activity of the compound, it is only a starting point. For example, further substantive experiments are necessary to provide a more comprehensive picture of each compound′s activity, the effect on the kinetics of the cell populations and subpopulations, and their potential mechanisms of action. Compounds have been tested with prepared donor spermatozoa, incubated under non-capacitating conditions, and only incubated with compounds for a relatively short period of time. Therefore, the effect of compounds under different conditions, for example in whole semen, for longer incubation times, or using samples from patient groups, may be different and require further study. All experiments were performed in vitro. This phenotypic screening assay identified a large number of compounds that increased sperm motility. In addition to furthering our understanding of human sperm function, for example identifying new avenues for discovery, we highlight potential compounds as promising start-point for a medicinal chem. program for potential enhancement of male fertility. Moreover, with disclosure of the results of screening, we present a substantial resource to inform further work in the field.

Human Reproduction published new progress about Drug discovery. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Electric Literature of 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Li, Hao; Sun, Wei; Huang, Xiuli; Lu, Xiao; Patel, Paresma R.; Kim, Myunghoon; Orr, Meghan J.; Fisher, Richard M.; Tanaka, Takeshi Q.; McKew, John C.; Simeonov, Anton; Sanderson, Philip E.; Zheng, Wei; Williamson, Kim C.; Huang, Wenwei published the artcile< Efficient Synthesis of 1,9-Substituted Benzo[h][1,6]naphthyridin-2(1H)-ones and Evaluation of their Plasmodium falciparum Gametocytocidal Activities>, HPLC of Formula: 1223001-51-1, the main research area is benzonaphthyridinone preparation antimalarial SAR bromochloroquinolinylacrylate tandem reaction aniline boronate; Torin; benzo[h][1,6]naphthyridin-2(1H)-ones; gametocytocidal activity; malaria; one-pot reaction; quinoline.

A novel three-component, two-step, 1-pot nucleophilic aromatic substitution (SNAr)-intramol. cyclization-Suzuki coupling reaction was developed for the synthesis of benzo[h][1,6]naphthyridin-2(1H)-ones (Torins). On the basis of the new efficiently convergent synthetic route, a library of Torin 2 analogs was synthesized. The antimalarial activities of these compounds were evaluated against asexual parasites using a growth inhibition assay and gametocytes using a viability assay.

ACS Combinatorial Science published new progress about Anilines Role: RCT (Reactant), RACT (Reactant or Reagent). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, HPLC of Formula: 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Shaik, Althaf; Bhakuni, Rashmi; Kirubakaran, Sivapriya published the artcile< Design, synthesis, and docking studies of new Torin2 analogs as potential ATR/mTOR kinase inhibitors>, COA of Formula: C24H15F3N4O, the main research area is Torin2 analog ATR mTOR inhibitor anticancer cancer QSAR; ATM; ATR; DNA damage and repair; docking; homology modeling; mTOR; molecular dynamic simulation; p-Chk1S317 (Ser 317), p70 S6KT389 (Thr 389).

Targeting DNA damage and response (DDR) pathway has become an attractive approach in cancer therapy. The key mediators involved in this pathway are ataxia telangiectasia-mutated kinase (ATM) and ataxia telangiectasia-mutated, Rad3-related kinase (ATR). These kinases induce cell cycle arrest in response to chemo- and radio-therapy and facilitate DNA repair via their major downstream targets. Targeting ATP-binding site of these kinases is currently under study. Torin2 is a second generation ATP competitive mTOR kinase inhibitor (EC50 = 250 pmol/L) with better pharmacokinetic profile. Torin2 also exhibits potent biochem. and cellular activity against ATM (EC50 = 28 nmol/L) and ATR (EC50 = 35 nmol/L) kinases. In this study, eight new Torin2 analogs were designed and synthesized through multistep synthesis. All the synthesized compounds were characterized by NMR and mass anal. The newly synthesized analogs were evaluated for their anti-cancer activity via CellTiter-Glo assay. Addnl., compounds 13 and 14 also showed significant inhibition for ATR and mTOR substrates, i.e., p-Chk1 Ser 317 and p70 S6K Thr 389, resp. Compounds 13 and 14 displayed promising anti-cancer activity with HCT-116 cell lines in the preliminary study. Further, a comparative model of ATR kinase was generated using the SWISS-MODEL server and validated using PROCHECK, ProSA anal. Synthesized compounds were docked into the ATP-binding site to understand the binding modes and for the rational design of new inhibitors.

Molecules published new progress about Antitumor agents. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, COA of Formula: C24H15F3N4O.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Liu, Qingsong; Xu, Chunxiao; Kirubakaran, Sivapriya; Zhang, Xin; Hur, Wooyoung; Liu, Yan; Kwiatkowski, Nicholas P.; Wang, Jinhua; Westover, Kenneth D.; Gao, Peng; Ercan, Dalia; Niepel, Mario; Thoreen, Carson C.; Kang, Seong A.; Patricelli, Matthew P.; Wang, Yuchuan; Tupper, Tanya; Altabef, Abigail; Kawamura, Hidemasa; Held, Kathryn D.; Chou, Danny M.; Elledge, Stephen J.; Janne, Pasi A.; Wong, Kwok-Kin; Sabatini, David M.; Gray, Nathanael S. published the artcile< Characterization of Torin2, an ATP-Competitive Inhibitor of mTOR, ATM, and ATR>, Safety of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one, the main research area is torin 2 antitumor mTOR ATM ATR colorectal breast cancer.

MTOR is a highly conserved serine/threonine protein kinase that serves as a central regulator of cell growth, survival, and autophagy. Deregulation of the PI3K/Akt/mT0R signaling pathway occurs commonly in cancer and numerous inhibitors targeting the ATP-binding site of these kinases are currently undergoing clin. evaluation. Here, we report the characterization of Torin2, a second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. Torin2 inhibited mTORCl-dependent T389 phosphorylation on S6K (RPS6KB1) with an EC50 of 250 pmol/L with approx. 800-fold selectivity for cellular mTOR vs. phosphoinositide 3-kinase (PI3K). Torin2 also exhibited potent biochem. and cellular activity against phosphatidylinositol-3 kinase-like kinase (PIKK) family kinases including ATM (EC50, 28 nmol/L), ATR (EC50, 35 nmol/L), and DNA-PK (EC50, 118 nmol/L; PRKDC), the inhibition of which sensitized cells to Irradiation Similar to the earlier generation compound Torinl and in contrast to other reported mTOR inhibitors, Torin2 inhibited mTOR kinase and mTORCl signaling activities in a sustained manner suggestive of a slow dissociation from the kinase. Cancer cell treatment with Torin2 for 24 h resulted in a prolonged block in neg. feedback and consequent T308 phosphorylation on Akt. These effects were associated with strong growth inhibition in vitro. Single-agent treatment with Torin2 in vivo did not yield significant efficacy against KRAS-driven lung tumors, but the combination of Torin2 with mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor AZD6244 yielded a significant growth inhibition. Taken together, our findings establish Torin2 as a strong candidate for clin. evaluation in a broad number of oncol. settings where mTOR signaling has a pathogenic role.

Cancer Research published new progress about Animal gene, c-Ki-ras Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Safety of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Montane, Marie-Helene; Menand, Benoit published the artcile< ATP-competitive mTOR kinase inhibitors delay plant growth by triggering early differentiation of meristematic cells but no developmental patterning change>, SDS of cas: 1223001-51-1, the main research area is ATP competitive mTOR kinase inhibitor plant growth meristem differentiation; ATP-competitive mTOR kinase inhibitors; Arabidopsis; Lotus; Nicotiana; cell size; differentiation; meristem; millet; rice; root growth; root hairs; target of rapamycin..

The TOR (target of rapamycin) protein, a large phosphatidylinositol 3-kinase-like protein kinase (PIKK) that is conserved in eukaryotes and is a central regulator of growth and metabolism The anal. of function of TOR in plant growth and development has been limited by the fact that plants are very poorly sensitive to rapamycin. As the kinase domain of TOR is highly conserved, this study analyzed the dose-dependent effect of three sets of first- and second-generation ATP-competitive inhibitors (called asTORis for active-site TOR inhibitors) recently developed for the human TOR kinase on Arabidopsis thaliana growth. All six asTORis inhibited plant root growth in a dose-dependent manner, with 50% growth inhibitory doses (GI50) of <10 μM and <1 μM for the first- and second-generation inhibitors, resp., similarly to the values in mammalian cells. A genetic approach further demonstrated that only asTORis inhibited root growth in an AtTOR gene-dosage-dependent manner. AsTORis decreased the length of: (i) the meristematic zone (MZ); (ii) the division zone in the MZ; (iii) epidermal cells in the elongation zone; and (iv) root hair cells. Whereas meristematic cells committed to early differentiation, the pattern of cell differentiation was not affected per se. AsTORis-induced root hair growth phenotype was shown to be specific by using other growth inhibitors blocking the cell cycle or translation. AsTORis dose-dependent inhibition of growth and root hairs was also observed in diverse groups of flowering plants, indicating that asTORis can be used to study the TOR pathway in other angiosperms, including crop plants. Journal of Experimental Botany published new progress about Arabidopsis thaliana. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, SDS of cas: 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Kowalski, Elizabeth; Geng, Shuo; Rathes, Allison; Lu, Ran; Li, Liwu published the artcile< Toll-interacting protein differentially modulates HIF1α and STAT5-mediated genes in fibroblasts>, Safety of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one, the main research area is inflammation infection Toll interacting protein HIF1alpha STAT5 gene fibroblast; gene expression profile inflammatory cytokine IL6 IL12 TNFalpha FABP4; fibroblast; gene expression; inflammation; innate immunity; signal transduction.

Toll-interacting protein (Tollip) deficiency has been implicated in complex inflammatory and infectious diseases whose mechanisms are poorly understood. Comparing the gene expression profiles of WT and Tollip-deficient murine embryonic fibroblasts, we observed here that Tollip deficiency selectively reduces the expression of the inflammatory cytokines interleukin 6 (IL-6), IL-12, and tumor necrosis factor α (TNFα) but potentiates the expression of fatty acid-binding protein 4 (FABP4) in these cells. We also observed that expression of hypoxia-inducible factor 1-α (HIF1α) is reduced, whereas that of signal transducer and activator of transcription 5 (STAT5) is elevated, in Tollip-deficient cells, correlating with the decreased expression of inflammatory cytokines and increased expression of FABP4 in these cells. We further found that the coupling of ubiquitin to ER degradation (CUE) domain of Tollip is required for stimulating HIF1α activity, because Tollip CUE-domain mutant cells exhibited reduced levels of HIF1α and selected cytokines. Tollip is known to mediate autophagy and lysosome fusion, and herein we observed that Tollip’s autophagy function is required for modulating STAT5 and FABP4 expression. Bafilomycin A, an inhibitor of lysosome fusion, enhanced STAT5 and FABP4 expression in WT fibroblasts, whereas torin 2, an activator of autophagy, reduced STAT5 and FABP4 expression in Tollip-deficient fibroblasts. Taken together, our study reveals that Tollip differentially modulates HIF1α and STAT5 expression in fibroblasts, potentially explaining the complex and context-dependent contribution of Tollip to disease development.

Journal of Biological Chemistry published new progress about Autophagy (lysosome fusion). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Safety of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Balukoff, Nathan C.; Ho, J. J. David; Theodoridis, Phaedra R.; Wang, Miling; Bokros, Michael; Llanio, Lis M.; Krieger, Jonathan R.; Schatz, Jonathan H.; Lee, Stephen published the artcile< A translational program that suppresses metabolism to shield the genome>, Application of C24H15F3N4O, the main research area is genome metabolism translational program.

Translatome reprogramming is a primary determinant of protein levels during stimuli adaptation. This raises the question: what are the translatome remodelers that reprogram protein output to activate biochem. adaptations. Here, we identify a translational pathway that represses metabolism to safeguard genome integrity. A system-wide MATRIX survey identified the ancient eIF5A as a pH-regulated translation factor that responds to fermentation-induced acidosis. TMT-pulse-SILAC anal. identified several pH-dependent proteins, including the mTORC1 suppressor Tsc2 and the longevity regulator Sirt1. Sirt1 operates as a pH-sensor that deacetylates nuclear eIF5A during anaerobiosis, enabling the cytoplasmic export of eIF5A/Tsc2 mRNA complexes for translational engagement. Tsc2 induction inhibits mTORC1 to suppress cellular metabolism and prevent acidosis-induced DNA damage. Depletion of eIF5A or Tsc2 leads to metabolic re-initiation and proliferation, but at the expense of incurring substantial DNA damage. We suggest that eIF5A operates as a translatome remodeler that suppresses metabolism to shield the genome.

Nature Communications published new progress about Acidosis. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Application of C24H15F3N4O.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Gurung, Arun Bahadur; Ali, Mohammad Ajmal; Lee, Joongku; Abul Farah, Mohammad; Al-Anazi, Khalid Mashay published the artcile< Unravelling lead antiviral phytochemicals for the inhibition of SARS-CoV-2 Mpro enzyme through in silico approach>, Related Products of 6882-68-4, the main research area is COVID 19 coronavirus protease inhibition phytochem; Antiviral properties; Binding affinity; COVID-19; Medicinal plants; Molecular docking; Phytochemicals; SARS-CoV-2; SARS-CoV-2 M(pro).

A new SARS coronavirus (SARS-CoV-2) belonging to the genus Betacoronavirus has caused a pandemic known as COVID-19. Among coronaviruses, the main protease (Mpro) is an essential drug target which, along with papain-like proteases catalyzes the processing of polyproteins translated from viral RNA and recognizes specific cleavage sites. There are no human proteases with similar cleavage specificity and therefore, inhibitors are highly likely to be nontoxic. Therefore, targeting the SARS-CoV-2 Mpro enzyme with small mols. can block viral replication. The present study is aimed at the identification of promising lead mols. for SARS-CoV-2 Mpro enzyme through virtual screening of antiviral compounds from plants. The binding affinity of selected small drug-like mols. to SARS-CoV-2 Mpro, SARS-CoV Mpro, and MERS-CoV Mpro were studied using mol. docking. Bonducellpin D was identified as the best lead mol. which shows higher binding affinity (-9.28 kcal/mol) as compared to the control (-8.24 kcal/mol). The mol. binding was stabilized through 4 hydrogen bonds with Glu166 and Thr190 as well as hydrophobic interactions via 8 residues. The SARS-CoV-2 Mpro shows identities of 96.08% and 50.65% to that of SARS-CoV Mpro and MERS-CoV Mpro resp. at the sequence level. At the structural level, the root mean square deviation (RMSD) between SARS-CoV-2 Mpro and SARS-CoV Mpro was found to be 0.517 Å and 0.817 Å between SARS-CoV-2 Mpro and MERS-CoV Mpro. Bonducellpin D exhibited broad-spectrum inhibition potential against SARS-CoV Mpro and MERS-CoV Mpro and therefore is a promising drug candidate, which needs further validations through in vitro and in vivo studies.

Life Sciences published new progress about Antiviral agents. 6882-68-4 belongs to class naphthyridine, and the molecular formula is C15H24N2O, Related Products of 6882-68-4.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Wang, Juan; Du, Tongde; Lu, Ya; Lv, Yan; Du, Yuxin; Wu, Jianzhong; Ma, Rong; Xu, Chenxin; Feng, Jifeng published the artcile< VLX1570 regulates the proliferation and apoptosis of human lung cancer cells through modulating ER stress and the AKT pathway>, Safety of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one, the main research area is AKT endoplasmic reticulum stress human lung cancer proliferation apoptosis; cell proliferation endoplasmic reticulum stress AKT pathway; AKT pathway; ER stress; VLX1570; apoptosis; lung cancer; proliferation.

The ubiquitin-proteasome system (UPS) possesses unique functions in tumorigenesis and has great potential for targeting tumors. The effectiveness of inhibitors targeting UPS in solid tumors remains to be studied. We screened a library of inhibitors targeting the ubiquitination system and found the highly potent, low-concentration inhibitor mol. VLX1570 that specifically killed lung cancer cells. VLX1570 is an inhibitor of deubiquitinating enzyme activity and has also shown potential for preclin. cancer treatment. We found that VLX1570 significantly inhibited lung cancer cells proliferation and colony formation. VLX1570 induced a G2/M cell cycle arrest by downregulating CDK1 and CyclinB1. Moreover, VLX1570 significantly promoted the mitochondrial-associated apoptosis. Mechanistically speaking, VLX1570 activated the PERK/IRE1/ATF6 pathway and induced ER stress in lung cancer cell lines. The inhibition of ER stress by tauroursodeoxycholic acid sodium or 4-phenylbutyric acid enhanced VLX1570-induced apoptosis. In addition, VLX1570 treatment led to the inactivation of Akt signalling and inhibited the proliferation of lung cancer cells by downregulating the Akt pathway. Moreover, combined treatment with VLX1570 and Afatinib or Gefitinib induced synergistic anti-lung cancer activity. Our present study demonstrated a novel therapy using VLX1570, which inhibited the proliferation and increased apoptosis in human lung cancer.

Journal of Cellular and Molecular Medicine published new progress about Activating transcription factor 6α Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Safety of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem