Category: 1223001-51-1

Udayakumar, Durga; Pandita, Raj K.; Horikoshi, Nobuo; Liu, Yan; Liu, Qingsong; Wong, Kwok-Kin; Hunt, Clayton R.; Gray, Nathanael S.; Minna, John D.; Pandita, Tej K.; Westover, Kenneth D. published the artcile< Torin2 suppresses ionizing radiation-induced DNA damage repair>, Electric Literature of 1223001-51-1, the main research area is ionizing radiation Torin2 mTOR inhibitor DNA damage repair cancer.

Several classes of inhibitors of the mammalian target of rapamycin (mTOR) have been developed based on its central role in sensing growth factor and nutrient levels to regulate cellular metabolism However, its ATP-binding site closely resembles other phosphatidylinositol 3-kinase-related kinase (PEKK) family members, resulting in reactivity with these targets that may also be therapeutically useful. The ATP- competitive mTOR inhibitor, Torin2, shows biochem. activity against the DNA repair-associated proteins ATM, ATR and DNA-PK, which raises the possibility that Torin2 and related compounds might radiosensitize cancerous tumors. In this study Torin2 was also found to enhance ionizing radiation-induced cell killing in conditions where ATM was dispensable, confirming the requirement for multiple PIKK targets. Moreover, Torin2 did not influence the initial appearance of γ-H2AX foci after irradiation but significantly delayed the disappearance of radiation-induced γ-H2AX foci, indicating a DNA repair defect. Torin2 increased the number of radiation-induced S-phase specific chromosome aberrations and reduced the frequency of radiation-induced CLIP and Rad51 foci formation, suggesting that Torin2 works by blocking homologous recombination (HR)-mediated DNA repair resulting in an S-phase specific DNA repair defect. We conclude that radiosensitization of tumor cells by Torin2 is associated with disrupting ATR- and ATM-dependent DNA damage responses.

Radiation Research published new progress about Attenuated total reflection. 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

Jhanwar-Uniyal, Meena; Dominguez, Jose F.; Mohan, Avinash L.; Tobias, Michael E.; Gandhi, Chirag D. published the artcile< Disentangling the signaling pathways of mTOR complexes, mTORC1 and mTORC2, as a therapeutic target in glioblastoma>, SDS of cas: 1223001-51-1, the main research area is glioblastoma therapeutic target disentangling signaling mTORC1 mTORC2; Glioblastoma; mTOR; mTORC1 mTORC2.

Aberrant signaling of mechanistic target of rapamycin (mTOR′ aka mammalian target of rapamycin) is shown to be linked to tumorigenesis of numerous malignancies including glioblastoma (GB). Glioblastoma mTOR is a serine threonine kinase that functions by forming two multiprotein complexes. There complexes are named mTORC1 and mTORC2 and downstream activated substrate execute cellular and metabolic functions. This signaling cascade of PI3K/AKT/mTOR is often upregulated due to frequent loss of the tumor suppressor PTEN, a phosphatase that functions antagonistically to PI3K. mTOR regulates cell growth, motility, and metabolism by forming two multiprotein complexes, mTORC1 and mTORC2, which are composed of special binding partners. These complexes are sensitive to distinct stimuli. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling. Since rapamycin and its analog are less effective in treatment of GB, we used novel ATP-competitive dual inhibitors of mTORC1 and mTORC2, namely, Torin1, Torin2, and XL388. Torin1 showed similar effects only at higher doses. Another small mol. compound, XL388 suppressed cell proliferation at a higher dose but failed to inhibit cell migration. In addition, formulation of third generation mTOR inhibitor “”Rapalink-1″” may provide new aspects to target mTOR pathways. Numerous inhibitors are currently being used in clin. trials that are aimed to target activated mTOR pathways.

Advances in Biological Regulation published new progress about AKT-interacting protein AKTIP Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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

Zamfirescu, Radu C.; Day, Margot L.; Morris, Michael B. published the artcile< mTORC1/2 signaling is downregulated by amino acid-free culture of mouse preimplantation embryos and is only partially restored by amino acid readdition>, Formula: C24H15F3N4O, the main research area is mTORC1 mTORC2 signaling amino acid mouse preimplantation embryo; Akt; amino acids; mTORC1; mouse preimplantation embryo; proline.

Development of the mammalian preimplantation embryo is influenced by autocrine/paracrine factors and the availability of nutrients. Deficiencies of these during in vitro culture reduce the success of assisted reproductive technologies. The mechanistic target of rapamycin complex 1 (mTORC1) pathway integrates external and internal signals, including those by amino acids (AAs), to promote normal preimplantation development. For this reason, AAs are often included in embryo culture media. In this study, we examined how withdrawal and addition of AAs to culture media modulate mTORC1 pathway activity compared with its activity in mouse embryos developed in vivo. Phosphorylation of signaling components downstream of mTORC1, namely, p70 ribosomal protein S6 kinase (p70S6K), ribosomal protein S6, and 4E binding protein 1 (4E-BP1), and that of protein kinase B (Akt), which lies upstream of mTORC1, changed significantly across stages of embryos developed in vivo. For freshly isolated blastocysts placed in vitro, the absence of AAs in the culture medium, even for a few hours, decreased mTORC1 signaling, which could only be partially restored by their addition Long-term culture of early embryos to blastocysts in the absence of AAs decreased mTORC1 signaling to a greater extent and again this could only be partially restored by their inclusion. This failure to fully restore is probably due to decreased phosphatidylinositol 3-kinase (PI3K)/Akt/mTORC2 signaling in culture, as indicated by decreased P-AktS473. MTORC2 lies upstream of mTORC1 and is insensitive to AAs, and its reduced activity probably results from loss of maternal/autocrine factors. These data highlight reduced mTORC1/2 signaling activity correlating with compromised development in vitro and show that the addition of AAs can only partially offset these effects.

American Journal of Physiology published new progress about Actins Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Formula: C24H15F3N4O.

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

Blazejewski, Sara M.; Bennison, Sarah A.; Liu, Xiaonan; Toyo-oka, Kazuhito published the artcile< High-throughput kinase inhibitor screening reveals roles for Aurora and Nuak kinases in neurite initiation and dendritic branching>, SDS of cas: 1223001-51-1, the main research area is high throughput screening aurora nuak kinase inhibitor neurite initiation.

Kinases are essential regulators of a variety of cellular signaling processes, including neurite formation-a foundational step in neurodevelopment. Aberrant axonal sprouting and failed regeneration of injured axons are associated with conditions like traumatic injury, neurodegenerative disease, and seizures. Investigating the mechanisms underlying neurite formation will allow for identification of potential therapeutics. We used a kinase inhibitor library to screen 493 kinase inhibitors and observed that 45% impacted neuritogenesis in Neuro2a (N-2a) cells. Based on the screening, we further investigated the roles of Aurora kinases A, B, and C and Nuak kinases 1 and 2. The roles of Aurora and Nuak kinases have not been thoroughly studied in the nervous system. Inhibition or overexpression of Aurora and Nuak kinases in primary cortical neurons resulted in various neuromorphol. defects, with Aurora A regulating neurite initiation, Aurora B and C regulating neurite initiation and elongation, all Aurora kinases regulating arborization, and all Nuak kinases regulating neurite initiation and elongation and arborization. Our high-throughput screening and anal. of Aurora and Nuak kinases revealed their functions and may contribute to the identification of therapeutics.

Scientific Reports published new progress about Aurora kinase inhibitors. 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

Song, Limei; Xu, Guoyun; Li, Tingting; Zhou, Huina; Lin, Qinlu; Chen, Jia; Wang, Long; Wu, Dousheng; Li, Xiaoxu; Wang, Lifeng; Zhu, Sirui; Yu, Feng published the artcile< The RALF1-FERONIA complex interacts with and activates TOR signaling in response to low nutrients>, COA of Formula: C24H15F3N4O, the main research area is TOR signaling RALF1 FERONIA complex; FERONIA; TOR; amino acid response; energy metabolism; nitrogen response.

Target of rapamycin (TOR) kinase is an evolutionarily conserved major regulator of nutrient metabolism and organismal growth in eukaryotes. In plants, nutrients are remobilized and reallocated between shoots and roots under low-nutrient conditions, and nitrogen and nitrogen-related nutrients (e.g., amino acids) are key upstream signals leading to TOR activation in shoots under low-nutrient conditions. However, how these forms of nitrogen can be sensed to activate TOR in plants is still poorly understood. Here we report that the Arabidopsis receptor kinase FERONIA (FER) interacts with the TOR pathway to regulate nutrient (nitrogen and amino acid) signaling under low-nutrient conditions and exerts similar metabolic effects in response to nitrogen deficiency. We found that FER and its partner, RPM1-induced protein kinase (RIPK), interact with the TOR/RAPTOR complex to pos. modulate TOR signaling activity. During this process, the receptor complex FER/RIPK phosphorylates the TOR complex component RAPTOR1B. The RALF1 peptide, a ligand of the FER/RIPK receptor complex, increases TOR activation in the young leaf by enhancing FER-TOR interactions, leading to promotion of true leaf growth in Arabidopsis under low-nutrient conditions. Furthermore, we showed that specific amino acids (e.g., Gln, Asp, and Gly) promote true leaf growth under nitrogen-deficient conditions via the FER-TOR axis. Collectively, our study reveals a mechanism by which the RALF1-FER pathway activates TOR in the plant adaptive response to low nutrients and suggests that plants prioritize nutritional stress response over RALF1-mediated inhibition of cell growth under low-nutrient conditions.

Molecular Plant published new progress about Alkaloids Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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

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

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

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

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

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