Category: naphthyridine

Hussain, Azhar R.; Al-Romaizan, Maha; Ahmed, Maqbool; Thangavel, Saravanan; Al-Dayel, Fouad; Beg, Shaham; Uddin, Shahab; Siraj, Abdul K.; Al-Kuraya, Khawla S. published the artcile< Dual targeting of mTOR activity with Torin2 potentiates anticancer effects of cisplatin in epithelial ovarian cancer>, Electric Literature of 1223001-51-1, the main research area is Torin2 cisplatin antitumor mTOR signaling epithelial ovarian cancer.

Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) are two key components of PI3K/Akt/mTOR signaling pathway. Dysregulation of these pathways have been found in many cancers, including epithelial ovarian cancer (EOC), however, the role of mTOR has not been fully elucidated in Middle Eastern EOC. Therefore, we investigated the activation of mTOR complexes (mTORC1 and mTORC2) in a cohort of 156 EOC from Saudi Arabia by immunohistochem. in a tissue microarray format. mTORC1 and mTORC2 were found to be activated in 55 of 146 (37.7%) and 63 of 140 (45%) of EOC samples, resp. mTORC1 was significantly associated with mTORC2 (p < 0.0001) activation and both mTOR complexes were significantly associated with p-AKT (p = 0.0205 and 0.0298) and p-P70S6 (p < 0.0001 and 0.0035), resp. Interestingly, mTOR activation incurred a poor progression-free survival (PFS) (p = 0.0188) in EOC. Next, the in vitro effect of inactivation of mTOR complexes was evaluated using a second-generation mTOR inhibitor, Torin2, on a panel of EOC cell lines. Torin2 treatment decreased cell viability and induced apoptosis in a dose-dependent manner via inactivation of mTORC1 and mTORC2 and their downstream targets in EOC cell lines. Furthermore, treatment of EOC cells with a subtoxic dose of Torin2 potentiated a cisplatin-induced apoptotic response in EOC cell lines. Finally, we studied the in vivo effect of a combination of Torin2 and cisplatin and found that this combination synergistically inhibited tumor growth in nude mice. These studies highlight the importance of targeting the mTOR survival pathway and suggest that cotreatment with cisplatin and Torin2 may be beneficial for the management of EOC. Molecular Medicine (Manhasset, NY, United States) published new progress about Antitumor agents. 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

Valenciano, Ana L.; Ramsey, Aaron C.; Santos, Webster L.; Mackey, Zachary B. published the artcile< Discovery and antiparasitic activity of AZ960 as a Trypanosoma brucei ERK8 inhibitor>, Product Details of C24H15F3N4O, the main research area is AZ960 trypanosomiasis trypanosomicide trypanosoma ERK8 inhibitor; AZ960; Extracellular-signal regulated kinase (ERK); High-throughput screening; Mitogen-activated protein kinase (MAPK); Trypanosoma brucei.

Human African trypanosomiasis (HAT) is a lethal, vector-borne disease caused by the parasite Trypanosoma brucei. Therapeutic strategies for this neglected tropical disease suffer from disadvantages such as toxicity, high cost, and emerging resistance. Therefore, new drugs with novel modes of action are needed. The authors screened cultured T. brucei against a focused kinase inhibitor library to identify promising bioactive compounds Among the ten hits identified from the phenotypic screen, AZ960 I emerged as the most promising compound with potent antiparasitic activity (IC50 = 120 nM) and was shown to be a selective inhibitor of an essential gene product, T. brucei extracellular signal-regulated kinase 8 (TbERK8). The authors report that AZ960 has a Ki of 1.25 μM for TbERK8 and demonstrate its utility in establishing TbERK8 as a potentially druggable target in T. brucei.

Bioorganic & Medicinal Chemistry published new progress about Chagas disease. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Product Details of C24H15F3N4O.

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

Luo, Jia; Pi, Guocheng; Xiao, He; Ye, Yunfei; Li, Qing; Zhao, Lianhua; Huang, Huan; Luo, Hong; Zhang, Qin; Wang, Dong; Wang, Ge published the artcile< Torin2 enhances the radiosensitivity of MCF-7 breast cancer cells by downregulating the mTOR signaling pathway and ATM phosphorylation>, Electric Literature of 1223001-51-1, the main research area is X ray Torin mTOR inhibitor radiosensitivity ATM breast cancer.

Radiotherapy has an important role in the comprehensive treatment of breast cancer. However, the clin. outcome of adjuvant radiotherapy may be limited due to intrinsic radioresistance, it is necessary to explore efficient radiosensitization methods that improve the clin. outcome of patients undergoing radiotherapy. The present study aimed to investigate whether the novel mechanistic target of rapamycin (mTOR) inhibitor Torin2 enhances the radiosensitivity of MCF-7 breast cancer cells. A Cell Counting Kit-8 (CCK-8) assay was performed to measure the effect of Torin2 on cell proliferation, while clonogenic assays were employed to determine the effect of Torin2 in combination with radiation on the proliferation of MCF-7 cells. The effect of Torin2 and/or radiation on the cell cycle was analyzed using flow cytometry. Furthermore, the protein expression of components of the phosphatidylinositol 3-kinase/Akt/mTOR pathway, and the expression of proteins involved in DNA damage repair, was measured by western blot anal. The results demonstrated that Torin2 exhibited a higher potency in MCF-7 cells, while MDA-MB-231 cells were less sensitive to Torin2. Compared with irradiation alone, pretreatment with 20 nM Torin2 followed by irradiation resulted in an increased level of γ-H2A histone family member X. Radiation induced the activation of the Akt/mTOR signaling pathway and upregulated the expression of phosphorylated (p)-Akt473 and p-eukaryotic translation initiation factor 4E binding protein 1 (4EBP1)37/46. Notably, pretreatment with Torin2 attenuated the radiation-induced activation of the Akt/mTOR signaling pathway. In addition, Torin2 partially blocked the repair of double-strand breaks induced by radiation by reducing the activation of ataxia telangiectasia-mutated, and sensitized MCF-7 cells to radiation. In conclusion, administration of Torin2 prior to irradiation enhanced the radiotherapeutic effect on breast cancer cells in vitro, and these results may provide a foundation for the rational use of combined therapy with irradiation and Torin2 for breast cancer in clin. practice.

Molecular Medicine Reports published new progress about Cell cycle checkpoint. 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

Hu, Chunhui; Gan, Xuehui; Jia, Qiangqiang; Gao, Pan; Du, Tao; Zhang, Fabin published the artcile< Optimization of supercritical-CO2 extraction and pharmacokinetics in SD rats of alkaloids form Sophora moorcroftiana seed>, Category: naphthyridine, the main research area is Sophora alkaloid carbon dioxide extraction pharmacokinetics optimization.

The total alkaloids extracted from the seeds of Sophora moorcroftiana (TAs-SM) have the potential to treat alveolar echinococcosis, a disease included by the WHO in a list of 17 key neglected diseases world-wide. The aims of the current study were first to develop a supercritical fluid extraction (SFE) method for optimizing TAs-SM extraction, and second, to develop an optimized method for evaluating TAs-SM pharmacokinetics in vivo. The Box-Behnken response surface method was used to optimize the extraction process, and ultra-high liquid chromatog. coupled with high resolution electrospray mass spectrometry (UPLC-HR-ESI-MS) was used to determine the pharmacokinetics of TAs-SM in SD rats. The results indicated the following optimal SFE extraction conditions: pressure = 31 MPa, temperature = 70 °C, time = 162.18 min. With these parameters, total alkaloids could be extracted from each gram of S. moorcroftiana, with the total content being 68.88 μg. The linear range of UPLC-HR-ESI-MS is 0.78-200.00 ng/mL, R2 > 0.99, and the sample recovery is 99-113%. The precision, accuracy, selectivity and stability of the method meet the requirements of US FDA guidelines. To our knowledge this study is the first to establish an SFE method for extracting TAs-SM and the first to employ UPLC-HR-ESI-MS for measuring TAs-SM in rats. These findings provide important contributions for using TAs-SM in further drug development and clin. applications.

Scientific Reports published new progress about Alkalinization. 6882-68-4 belongs to class naphthyridine, and the molecular formula is C15H24N2O, Category: naphthyridine.

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

Al-Ali, Hassan; Lemmon, Vance P.; Bixby, John L. published the artcile< Phenotypic screening of small-molecule inhibitors: implications for therapeutic discovery and drug target development in traumatic brain injury>, Category: naphthyridine, the main research area is TBI therapeutic discovery drug target inhibitor phenotypic screening; Axon regeneration; CNS injury; Cell-based assay; Drug discovery; High-content screening; Kinase inhibitor; Primary neurons.

The inability of central nervous system (CNS) neurons to regenerate damaged axons and dendrites following traumatic brain injury (TBI) creates a substantial obstacle for functional recovery. Apoptotic cell death, deposition of scar tissue, and growth-repressive mols. produced by glia further complicate the problem and make it challenging for re-growing axons to extend across injury sites. To date, there are no approved drugs for the treatment of TBI, accentuating the need for relevant leads. Cell-based and organotypic bioassays can better mimic outcomes within the native CNS microenvironment than target-based screening methods and thus should speed the discovery of therapeutic agents that induce axon or dendrite regeneration. Addnl., when used to screen focused chem. libraries such as small-mol. protein kinase inhibitors, these assays can help elucidate mol. mechanisms involved in neurite outgrowth and regeneration as well as identify novel drug targets. Here, we describe a phenotypic cellular (high content) screening assay that utilizes brain-derived primary neurons for screening small-mol. chem. libraries.

Methods in Molecular Biology (New York, NY, United States) published new progress about Antibodies and Immunoglobulins Role: BUU (Biological Use, Unclassified), BIOL (Biological Study), USES (Uses). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Category: naphthyridine.

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

Wang, Beilei; Deng, Yuanxin; Chen, Yongfei; Yu, Kailin; Wang, Aoli; Liang, Qianmao; Wang, Wei; Chen, Cheng; Wu, Hong; Hu, Chen; Miao, Weili; Hur, Wooyoung; Wang, Wenchao; Hu, Zhenquan; Weisberg, Ellen L.; Wang, Jinhua; Ren, Tao; Wang, Yinsheng; Gray, Nathanael S.; Liu, Qingsong; Liu, Jing published the artcile< Structure-activity relationship investigation for benzonaphthyridinone derivatives as novel potent Bruton's tyrosine kinase (BTK) irreversible inhibitors>, Synthetic Route of 1223001-51-1, the main research area is benzo naphthyridinone derivative structure preparation Bruton’s tyrosine kinase cancer; B-Cell lymphoma; BTK; Irreversible inhibitor; Kinase inhibitor; Structure-activity relationship.

Through a structure-based drug design approach, a tricyclic benzonaphthyridinone pharmacophore was used as a starting point for carrying out detailed medicinal structure-activity relationhip (SAR) studies geared toward characterization of a panel of proposed BTK inhibitors, including 6 (QL-X-138), 7 (BMX-IN-1) and 8 (QL47). These studies led to the discovery of the novel potent irreversible BTK inhibitor, compound 18 (CHMFL-BTK-11). Kinetic anal. of compound 18 revealed an irreversible binding efficacy (kinact/Ki) of 0.01 μM-1s-1. Compound 18 potently inhibited BTK kinase Y223 auto-phosphorylation (EC50 < 100 nM), arrested cell cycle in G0/G1 phase, and induced apoptosis in Ramos, MOLM13 and Pfeiffer cells. We believe these features would make 18 a good pharmacol. tool for studying BTK-related pathologies. European Journal of Medicinal Chemistry published new progress about Antiproliferative agents. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Synthetic Route of 1223001-51-1.

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

Roberts, Lindsay S.; Yan, Peter; Bateman, Leslie A.; Nomura, Daniel K. published the artcile< Mapping Novel Metabolic Nodes Targeted by Anti-Cancer Drugs that Impair Triple-Negative Breast Cancer Pathogenicity>, Recommanded Product: 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo[h][1,6]naphthyridin-2(1H)-one, the main research area is drug screening proteomic metabolomic profiling breast cancer pathogenicity.

Triple-neg. breast cancers (TNBCs) are estrogen receptor, progesterone receptor, and HER2 receptor-neg. subtypes of breast cancers that show the worst prognoses and lack targeted therapies. Here, we have coupled the screening of ∼400 anticancer agents that are under development or in the clinic with chemoproteomic and metabolomic profiling to identify novel metabolic mechanisms for agents that impair TNBC pathogenicity. We identify 20 anticancer compounds that significantly impaired cell survival across multiple types of TNBC cells. Among these 20 leads, the phytoestrogenic natural product licochalcone A was of interest, since TNBCs are unresponsive to estrogenic therapies, indicating that licochalcone A was likely acting through another target. Using chemoproteomic profiling approaches, we reveal that licochalcone A impairs TNBC pathogenicity, not through modulating estrogen receptor activity but rather through inhibiting prostaglandin reductase 1, a metabolic enzyme involved in leukotriene B4 inactivation. We also more broadly performed metabolomic profiling to map addnl. metabolic mechanisms of compounds that impair TNBC pathogenicity. Overlaying lipidomic profiling with drug responses, we find that deubiquitinase inhibitors cause dramatic elevations in acyl carnitine levels, which impair mitochondrial respiration and contribute to TNBC pathogenic impairments. We thus put forth two unique metabolic nodes that are targeted by drugs or drug candidates that impair TNBC pathogenicity. Our results also showcase the utility of coupling drug screens with chemoproteomic and metabolomic profiling to uncover unique metabolic drivers of TNBC pathogenicity.

ACS Chemical Biology published new progress about Antitumor agents. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Recommanded Product: 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

Tamir, Tigist Y.; Bowman, Brittany M.; Agajanian, Megan J.; Goldfarb, Dennis; Schrank, Travis P.; Stohrer, Trent; Hale, Andrew E.; Siesser, Priscila F.; Weir, Seth J.; Murphy, Ryan M.; LaPak, Kyle M.; Weissman, Bernard E.; Moorman, Nathaniel J.; Ben Major, M. published the artcile< Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor>, Category: naphthyridine, the main research area is nuclear erythroid transcription factor brain specific kinase human disease; AMPK; BRSK1; BRSK2; Functional genomics; Kinase; NRF2; Oxidative stress response; Phosphoproteomics; mTOR.

Nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) is a transcription factor and master regulator of cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, but conversely NRF2 activity diminishes with age and in neurodegenerative and metabolic disorders. Although NRF2-activating drugs are clin. beneficial, NRF2 inhibitors do not yet exist. Here, we describe use of a gain-of-function genetic screen of the kinome to identify new druggable regulators of NRF2 signaling. We found that the under-studied protein kinase brain-specific kinase 2 (BRSK2) and the related BRSK1 kinases suppress NRF2-dependent transcription and NRF2 protein levels in an activity-dependent manner. Integrated phosphoproteomics and RNAseq studies revealed that BRSK2 drives 5′-AMP-activated protein kinase α2 (AMPK) signaling and suppresses the mTOR pathway. As a result, BRSK2 kinase activation suppresses ribosome-RNA complexes, global protein synthesis and NRF2 protein levels. Collectively, our data illuminate the BRSK2 and BRSK1 kinases, in part by functionally connecting them to NRF2 signaling and mTOR. This signaling axis might prove useful for therapeutically targeting NRF2 in human disease.

Journal of Cell Science published new progress about Activating transcription factor 3 Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Category: naphthyridine.

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

Quiros-Fernandez, Isaac; Figueroa-Protti, Lucia; Arias-Arias, Jorge L.; Brenes-Cordero, Norman; Siles, Francisco; Mora, Javier; Mora-Rodriguez, Rodrigo Antonio published the artcile< Perturbation-Based Modeling Unveils the Autophagic Modulation of Chemosensitivity and Immunogenicity in Breast Cancer Cells>, Application In Synthesis of 1223001-51-1, the main research area is perturbation modeling unveil autophagic modulation chemosensitivity immunogenicity breast cancer; autophagy; chemotherapy; immunogenic cell death; perturbation-based modeling.

In the absence of new therapeutic strategies, chemotherapeutic drugs are the most widely used strategy against metastatic breast cancer, in spite of eliciting multiple adverse effects and having low responses with an average 5-yr patient survival rate. Among the new therapeutic targets that are currently in clin. trials, here, we addressed the association between the regulation of the metabolic process of autophagy and the exposure of damage-associated mol. patterns associated (DAMPs) to immunogenic cell death (ICD), which has not been previously studied. After validating an mCHR-GFP tandem LC3 sensor capacity to report dynamic changes of the autophagic metabolic flux in response to external stimuli and demonstrating that both basal autophagy levels and response to diverse autophagy regulators fluctuate among different cell lines, we explored the interaction between autophagy modulators and chemotherapeutic agents in regards of cytotoxicity and ICD using three different breast cancer cell lines. Since these interactions are very complex and variable throughout different cell lines, we designed a perturbation-based model in which we propose specific modes of action of chemotherapeutic agents on the autophagic flux and the corresponding strategies of modulation to enhance the response to chemotherapy. Our results point towards a promising therapeutic potential of the metabolic regulation of autophagy to overcome chemotherapy resistance by eliciting ICD.

Metabolites published new progress about Autophagosome. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Application In Synthesis of 1223001-51-1.

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

Dillenburg-Pilla, Patricia; Patel, Vyomesh; Mikelis, Constantinos M.; Zarate-Blades, Carlos Rodrigo; Doci, Colleen L.; Amornphimoltham, Panomwat; Wang, Zhiyong; Martin, Daniel; Leelahavanichkul, Kantima; Dorsam, Robert T.; Masedunskas, Andrius; Weigert, Roberto; Molinolo, Alfredo A.; Gutkind, J. Silvio published the artcile< SDF-1/CXCL12 induces directional cell migration and spontaneous metastasis via a CXCR4/Gαi/mTORC1 axis>, Formula: C24H15F3N4O, the main research area is CXCR4 Galphai mTORC1 axis SDF1 CXCL12 cell migration metastasis; cancer; chemotaxis; lymphangiogenesis; mTOR; rapamycin.

Multiple human malignancies rely on C-X-C motif chemokine receptor type 4 (CXCR4) and its ligand, SDF-1/CXCL12 (stroma cell-derived factor 1/C-X-C motif chemokine 12), to metastasize. CXCR4 inhibitors promote the mobilization of bone marrow stem cells, limiting their clin. application for metastasis prevention. We investigated the CXCR4-initiated signaling circuitry to identify new potential therapeutic targets. We used HeLa human cancer cells expressing high levels of CXCR4 endogenously. We found that CXCL12 promotes their migration in Boyden chamber assays and single cell tracking. CXCL12 activated mTOR (mechanistic target of rapamycin) potently in a pertussis-sensitive fashion. Inhibition of mTOR complex 1 (mTORC1) by rapamycin [drug concentration causing 50% inhibition (IC50) = 5 nM] and mTORC1/mTORC2 by Torin2 (IC50 = 6 nM), or by knocking down key mTORC1/2 components, Raptor and Rictor, resp., decreased directional cell migration toward CXCL12. We developed a CXCR4-mediated spontaneous metastasis model by implanting HeLa cells in the tongue of SCID-NOD mice, in which 80% of the animals develop lymph node metastasis. It is surprising that mTORC1 disruption by Raptor knockdown was sufficient to reduce tumor growth by 60% and spontaneous metastasis by 72%, which were nearly abolished by rapamycin. In contrast, disrupting mTORC2 had no effect in tumor growth or metastasis compared with control short hairpin RNAs. These data suggest that mTORC1 may represent a suitable therapeutic target in human malignancies using CXCR4 for their metastatic spread.

FASEB Journal published new progress about Angiogenesis. 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