Tag: M.W=400-600

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

Holditch, Sara J.; Brown, Carolyn N.; Atwood, Daniel J.; Lombardi, Andrew M.; Nguyen, Khoa N.; Toll, Harrison W.; Hopp, Katharina; Edelstein, Charles L. published the artcile< A study of sirolimus and mTOR kinase inhibitor in a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease>, Electric Literature of 1223001-51-1, the main research area is sirolimus mTOR kinase polycystic kidney disease; apoptosis; autosomal dominant polycystic kidney disease; polycystic; proliferation; sirolimus; torin2.

Autosomal dominant polycystic kidney disease (PKD) is characterized by cyst formation and growth, which are partially driven by abnormal proliferation of tubular cells. Proproliferative mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1 and mTORC2) are activated in the kidneys of mice with PKD. The aim of the present study was to determine the effects of sirolimus vs. the mTOR kinase inhibitor torin2 on cyst growth and kidney function in the Pkd1 p.R3277C (Pkd1RC/RC) mouse model, a hypomorphic Pkd1 model orthologous to the human condition, and to determine the effects of sirolimus vs. torin2 on mTORC1 and mTORC2 signaling in PKD1/ cells and in the kidneys of Pkd1RC/RC mice. In vitro, both inhibitors reduced mTORC1 and mTORC2 phosphorylated substrates and neg. impacted cellular metabolic activity, as measured by MTT assay. Pkd1RC/RC mice were treated with sirolimus or torin2 from 50 to 120 days of age. Torin2 was as effective as sirolimus in decreasing cyst growth and improving loss of kidney function. Both sirolimus and torin2 decreased phosphorylated S6 protein, phosphorylated eukaryotic translation initiation factor 4E-binding protein 1, phosphorylated Akt, and proliferation in Pkd1RC/RC kidneys. In conclusion, torin2 and sirolimus were equally effective in decreasing cyst burden and improving kidney function and mediated comparable effects on mTORC1 and mTORC2 signaling and proliferation in the Pkd1RC/RC kidney.

American Journal of Physiology published new progress about Animal gene, PKD1 Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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

Chen, Kuan-Chung; Lee, Wen-Yuan; Chen, Hsin-Yi; Chen, Calvin Yu-Chian published the artcile< In silico investigation of potential mTOR inhibitors from traditional Chinese medicine for treatment of Leigh syndrome>, Application of C24H15F3N4O, the main research area is human Leigh syndrome mTOR inhibitor traditional Chinese medicine.

A recent research demonstrates that the inhibition of mammalian target of rapamycin mTOR improves survival and health for patients with Leigh syndrome. mTOR proteins can be treated as drug target proteins against Leigh syndrome and other mitochondrial disorders. In this study, we aim to identify potent TCM compounds from the TCM Database@Taiwan as lead compounds of mTOR inhibitors. PONDR-Fit protocol was employed to predict the disordered disposition in mTOR protein before virtual screening. After virtual screening, the MD simulation was employed to validate the stability of interactions between each ligand and mTOR protein in the docking poses from docking simulation. The top TCM compounds, picrasidine M and acerosin, have higher binding affinities with target protein in docking simulation than control. There have H-bonds with residues Val2240 and π interactions with common residue Trp2239. After MD simulation, the top TCM compounds maintain similar docking poses under dynamic conditions. The top two TCM compounds, picrasidine M and acerosin, were extracted from Picrasma quassioides D. Don Benn. and Vitex negundo L. Hence, we propose the TCM compounds, picrasidine M and acerosin, as potential candidates as lead compounds for further study in drug development process with the mTOR protein against Leigh syndrome and other mitochondrial disorders.

BioMed Research International published new progress about Alangium lamarckii. 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

Atwood, Daniel J.; Pokhrel, Deepak; Brown, Carolyn N.; Holditch, Sara J.; Bachu, Dheevena M.; Thorburn, Andrew; Hopp, Katharina; Edelstein, Charles L. published the artcile< Increased mTOR and suppressed autophagic flux in the heart of a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease>, Application of C24H15F3N4O, the main research area is mTOR Pkd1 beclin1 polycystic kidney disease; Autophagy; Autosomal dominant polycystic kidney disease; Cardiac hypertrophy; Heart; mTOR.

Cardiac hypertrophy is common in autosomal dominant polycystic kidney disease (ADPKD) patients. We found increased heart weight in Pkd1RC/RC and Pkd2WS25/+ mouse models of ADPKD. As there is a link between increased heart weight and mammalian target of rapamycin (mTOR), the aim of the study was to determine mTOR complex 1 and 2 signaling proteins in the heart in the Pkd1RC/RC mouse model of PKD. In 70 day old Pkd1RC/RC hearts, on immunoblot anal., there was a large increase in p-AMPKThr172, a known autophagy inducer, and an increase in p-AktSer473 and p-AktThr308, but no increase in other mTORC1/2 proteins (p-S6Ser240/244, p-mTORSer2448). In 150 day old Pkd1RC/RC hearts, there was an increase in mTORC1 (p-S6Ser240/244) and mTOR-related proteins (p-AktThr308, p-GSK3βSer9, p-AMPKThr172). As the mTOR pathway is the master regulator of autophagy, autophagy proteins were measured. There was an increase in p-Beclin-1 (BECN1), an autophagy regulator and activating mol. in Beclin-1-regulated autophagy (AMBRA1), a regulator of Beclin that play a role in autophagosome formation, an early stage of autophagy. There was a defect in the later stage of autophagy, the fusion of the autophagosome with the lysosome, known as autophagic flux, as evidenced by the lack of an increase in LC3-II, a marker of autophagosomes, with the lysosomal inhibitor bafilomycin, in both 70 day old and 150 day old hearts. To determine the role of autophagy in causing increased heart weight, Pkd1RC/RC were treated with 2-deoxyglucose (2-DG) or Tat-Beclin1 peptide, agents known to induce autophagy. 2-DG treatment from 150 to 350 days of age, a time period when increased heart weight developed, did not reduce the increased heart weight Unexpectedly, Tat-Beclin 1 peptide treatment from 70 to 120 days of age resulted in increased heart weight In summary, there is suppressed autophagic flux in the heart at an early age in Pkd1RC/RC mice. Increased mTOR signaling in older mice is associated suppressed autophagic flux. There was a large increase in p-AMPKThr172, a known autophagy inducer, in both young and old mice. 2-DG treatment did not impact increased heart weight and Tat-Beclin1 peptide increased heart weight

Cellular Signalling published new progress about Adult, mammalian. 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

Bein, Kiflai; Ganguly, Koustav; Martin, Timothy M.; Concel, Vincent J.; Brant, Kelly A.; Di, Y. P. Peter; Upadhyay, Swapna; Fabisiak, James P.; Vuga, Louis J.; Kaminski, Naftali; Kostem, Emrah; Eskin, Eleazar; Prows, Daniel R.; Jang, Ann-Soo; Leikauf, George D. published the artcile< Genetic determinants of ammonia-induced acute lung injury in mice>, HPLC of Formula: 1223001-51-1, the main research area is genetic determinant ammonia acute lung injury mice; ARDS; acute lung injury; chemical threat; functional genomics; transcriptomics.

In this study, a genetically diverse panel of 43 mouse strains was exposed to ammonia, and genome-wide association mapping was performed employing a single-nucleotide polymorphism (SNP) assembly. Transcriptomic anal. was used to help resolve the genetic determinants of ammonia-induced acute lung injury. The encoded proteins were prioritized based on mol. function, nonsynonymous SNP within a functional domain or SNP within the promoter region that altered expression. This integrative functional approach revealed 14 candidate genes that included Aatf, Avil, Cep162, Hrh4, Lama3, Plcb4, and Ube2cbp, which had significant SNP associations, and Aff1, Bcar3, Cntn4, Kcnq5, Prdm10, Ptcd3, and Snx19, which had suggestive SNP associations Of these genes, Bcar3, Cep162, Hrh4, Kcnq5, and Lama3 are particularly noteworthy and had pathophysiol. roles that could be associated with acute lung injury in several ways.

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, HPLC of Formula: 1223001-51-1.

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

Xu, Fei; Li, Xin; Yan, Lili; Yuan, Na; Fang, Yixuan; Cao, Yan; Xu, Li; Zhang, Xiaoying; Xu, Lan; Ge, Chaorong; An, Ni; Jiang, Gaoyue; Xie, Jialing; Zhang, Han; Jiang, Jiayi; Li, Xiaotian; Yao, Lei; Zhang, Suping; Zhou, Daohong; Wang, Jianrong published the artcile< Autophagy promotes the repair of radiation-induced DNA damage in bone marrow hematopoietic cells via enhanced STAT3 signaling>, Product Details of C24H15F3N4O, the main research area is gamma radiation autophagy DNA damage BM hematopoietic cell.

Autophagy protects hematopoietic cells from radiation damage in part by promoting DNA damage repair. However, the mol. mechanisms by which autophagy regulates DNA damage repair remain largely elusive. Here, we report that this radioprotective effect of autophagy depends on STAT3 signaling in murine bone marrow mononuclear cells (BM-MNCs). Specifically, we found that STAT3 activation and nuclear translocation in BM-MNCs were increased by activation of autophagy with an mTOR inhibitor and decreased by knockout of the autophagy gene Atg7. The autophagic regulation of STAT3 activation is likely mediated by induction of KAP1 degradation, because we showed that KAP1 directly interacted with STAT3 in the cytoplasm and knockdown of KAP1 increased the phosphorylation and nuclear translocation of STAT3. Subsequently, activated STAT3 transcriptionally upregulated the expression of BRCA1, which increased the ability of BM-MNCs to repair radiation-induced DNA damage. This novel finding that activation of autophagy can promote DNA damage repair in BM-MNCs via the ATG-KAP1-STAT3-BRCA1 pathway suggests that autophagy plays an important role in maintaining genomic integrity of BM-MNCs and its activation may confer protection of BM-MNCs against radiationinduced genotoxic stress.

Radiation Research published new progress about Autophagy. 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

Chernoryzh, Ya. Yu.; Fedorova, N. E.; Yurlov, K. I.; Simonov, R. A.; Kornev, A. B.; Karpov, D. S.; Zakirova, N. F.; Ivanov, A. V.; Kushch, A. A.; Gintsburg, A. L. published the artcile< Resistance of THP-1 Leukemia Cells Infected with Cytomegalovirus to Anti-tumor Antibiotic Doxorubicin and Restoration of the Sensitivity by Inhibitors of the PI3K/AKT/mTOR Molecular Pathway>, Computed Properties of 1223001-51-1, the main research area is doxorubicin anticancer agent antibiotic PI3K cytomegalovirus leukemia.

Abstract: Results obtained showed that infection with HCMV prevented the death of THP-1 cells treated with DOX in both active and latent forms of infection. In the presence of mTOR inhibitors (rapamycin and Torin2), the sensitivity of the infected cells to DOX was restored. Rapamycin inhibited the expression of the HCMV protein IE1-p72 and increased sensitivity to DOX. Mol. targets for the creation of new drugs for the treatment of leukemia in patients infected with HCMV were determined

Doklady Biochemistry and Biophysics published new progress about Antibiotics Role: THU (Therapeutic Use), BIOL (Biological Study), USES (Uses). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Computed Properties of 1223001-51-1.

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

Wu, H.; Hu, C.; Wang, A.; Weisberg, E. L.; Chen, Y.; Yun, C.-H.; Wang, W.; Liu, Y.; Liu, X.; Tian, B.; Wang, J.; Zhao, Z.; Liang, Y.; Li, B.; Wang, L.; Wang, B.; Chen, C.; Buhrlage, S. J.; Qi, Z.; Zou, F.; Nonami, A.; Li, Y.; Fernandes, S. M.; Adamia, S.; Stone, R. M.; Galinsky, I. A.; Wang, X.; Yang, G.; Griffin, J. D.; Brown, J. R.; Eck, M. J.; Liu, J.; Gray, N. S.; Liu, Q. published the artcile< Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia>, Synthetic Route of 1223001-51-1, the main research area is lymphoma leukemia Bruton tyrosine kinase MNK dual inhibitor.

Bruton’s tyrosine kinase (BTK) kinase is a member of the TEC kinase family and is a key regulator of the B-cell receptor (BCR)-mediated signaling pathway. It is important for B-cell maturation, proliferation, survival and metastasis. Pharmacol. inhibition of BTK is clin. effective against a variety of B-cell malignances, such as mantle cell lymphoma, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and activated B-cell-diffuse large B-cell lymphoma. MNK kinase is one of the key downstream regulators in the RAF-MEK-ERK signaling pathway and controls protein synthesis via regulating the activity of eIF4E. Inhibition of MNK activity has been observed to moderately inhibit the proliferation of AML cells. Through a structure-based drug-design approach, we have discovered a selective and potent BTK/MNK dual kinase inhibitor (QL-X-138), which exhibits covalent binding to BTK and noncovalent binding to MNK. Compared with the BTK kinase inhibitor (PCI-32765) and the MNK kinase inhibitor (cercosporamide), QL-X-138 enhanced the antiproliferative efficacies in vitro against a variety of B-cell cancer cell lines, as well as AML and CLL primary patient cells, which respond moderately to BTK inhibitor in vitro. The agent can effectively arrest the growth of lymphoma and leukemia cells at the G0-G1 stage and can induce strong apoptotic cell death. These primary results demonstrate that simultaneous inhibition of BTK and MNK kinase activity might be a new therapeutic strategy for B-cell malignances.

Leukemia published new progress about Acute myeloid leukemia. 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

Hau, Andrew M.; Nakasaki, Manando; Nakashima, Kazufumi; Krish, Goutam; Hansel, Donna E. published the artcile< Differential mTOR pathway profiles in bladder cancer cell line subtypes to predict sensitivity to mTOR inhibition>, Formula: C24H15F3N4O, the main research area is mtor pathway bladder cancer cell line subtype inhibition; Basal; Bladder cancer; Cell lines; Luminal; mTOR; mTOR inhibitor.

Mol. classification of bladder cancer has been increasingly proposed as a potential tool to predict clin. outcomes and responses to chemotherapy. Here we focused on mechanistic target of rapamycin (mTOR) inhibition as a chemotherapeutic strategy and characterized the expression profile of mTOR signaling targets in representative bladder cancer cell lines from basal, luminal, and either basal/luminal (“”non-type””) mol. subtypes. Protein and mRNA expression of mTOR signaling components from representative luminal (RT4 and RT112), basal (SCaBER and 5637), and nontype (T24 and J82) bladder cancer cell line subtypes were determined by Western blot and database mining anal. of the Cancer Cell Line Encyclopedia. Cell viability following treatment with either, Torin-2 or KU-0063794, 2 dual mTOR complex 1/2 inhibitors, was determined by MTT assay. Immunoblot anal. of cells treated with Torin-2 or KU-0063794 was performed to determine the effects of mTOR inhibition on expression and phosphorylation status of mTOR signaling components, Akt, 4E-BP1, and ribosomal protein S6. Mol. subtypes of bladder cancer cell lines each exhibited a distinct pattern of expression of mTOR-associated genes and baseline phosphorylation level of Akt and 4E-BP1. Cells with low levels of Akt Ser-473 phosphorylation were more resistant to the cytotoxic effects of mTOR inhibition with Torin-2, but not KU-0063794. Exposure to Torin-2 and KU-0063794 both potently and rapidly inhibited phosphorylation of Akt Ser-473 and Thr-308, and 4E-BP1 T37/46 in cell lines that included basal and nontype subtypes. Differential gene expression and protein activity associated with mTOR signaling is observed among bladder cancer cell lines stratified into basal, luminal, and nontype subtypes. Urothelial carcinomas characterized by high baseline Akt Ser-473 phosphorylation may be best suited for targeted mTOR therapies.

Urologic Oncology: Seminars and Original Investigations 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

Hassett, Matthew R.; Sternberg, Anna R.; Roepe, Paul D. published the artcile< Inhibition of Human Class I vs Class III Phosphatidylinositol 3'-Kinases>, Quality Control of 1223001-51-1, the main research area is inhibition class I III isoenzyme phosphatidylinositol kinase PI3K.

Most investigations of phosphatidylinositol 3′-kinase (PI3K) drug inhibition have been via assays based on ADP appearance or ATP consumption (e.g. Liu, Q. et al. (2011) J. Med. Chem. 54, 1473-1480). However, at least some PI3K isoforms show basal ATPase activity in the absence of PI lipid substrate(s), which may complicate quantification of drug potency, isoform specificity of some drugs, and synergy for drug combinations. In this study, we probe the class I vs. class III isoform specificity of a selected set of phosphatidylinositol 3′-kinase (PI3K) inhibitors using a simple, inexpensive, semi high-throughput assay that quantifies production of phosphatidylinositol 3′-phosphate (PI3P) from phosphatidylinositol (PI). Results are compared to previous data largely generated using ATPase activity assays. Good agreement between EC50 values computed via ATPase assays vs. the reported PI3P formation assay is found for most drugs, but with a few exceptions. Also, for the first time, drug inhibition of class I vs. class III enzymes is compared side-by-side with the same assay for the important class I specific inhibitors GSK2126458 (“”Omipalisib””) and NVP-BGT226 (“”BGT226″”) currently in clin. development for advanced solid tumors.

Biochemistry published new progress about Enzyme inhibition kinetics. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Quality Control of 1223001-51-1.

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