Day: November 21, 2022

Tian, He-Ping published the artcileNon-receptor tyrosine kinase Src is required for ischemia-stimulated neuronal cell proliferation via Raf/ERK/CREB activation in the dentate gyrus, Recommanded Product: SU6656, the publication is BMC Neuroscience (2009), No pp. given, database is CAplus and MEDLINE.

Background: Neurogenesis in the adult mammalian hippocampus may contribute to repairing the brain after injury. However, Mol. mechanisms that regulate neuronal cell proliferation in the dentate gyrus (DG) following ischemic stroke insult are poorly understood. This study was designed to investigate the potential regulatory capacity of non-receptor tyrosine kinase Src on ischemia-stimulated cell proliferation in the adult DG and its underlying mechanism. Results: Src kinase activated continuously in the DG 24 h and 72h after transient global ischemia, while SU6656, the Src kinase inhibitor significantly decreased the number of bromodeoxyuridine (BrdU) labeling-pos. cells of rats 7 days after cerebral ischemia in the DG, as well as down-regulated Raf phosphorylation at Tyr(340/341) site, and its down-stream signaling mols. ERK and CREB expression followed by 24 h and 72h of reperfusion, suggesting a role of Src kinase as an enhancer on neuronal cell proliferation in the DG via modifying the Raf/ERK/CREB cascade. This hypothesis is supported by further findings that U0126, the ERK inhibitor, induced a reduction of adult hippocampal progenitor cells in DG after cerebral ischemia and down-regulated phospho-ERK and phospho-CREB expression, but no effect was detected on the activities of Src and Raf. Conclusion: Src kinase increase numbers of newborn neuronal cells in the DG via the activation of Raf/ERK/CREB signaling cascade after cerebral ischemia.

BMC Neuroscience published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C11H21BF4N2O2, Recommanded Product: SU6656.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Teng, Christina T. published the artcileDevelopment of Novel Cell Lines for High-Throughput Screening to Detect Estrogen-Related Receptor Alpha Modulators, Synthetic Route of 330161-87-0, the publication is SLAS Discovery (2017), 22(6), 720-731, database is CAplus and MEDLINE.

Estrogen-related receptor alpha (ERRα), the first orphan nuclear receptor discovered, is crucial for the control of cellular energy metabolism ERRα and its coactivator, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), are required for rapid energy production in response to environmental challenges. They have been implicated in the etiol. of metabolic disorders such as type 2 diabetes and metabolic syndrome. ERRα also plays a role in the pathogenesis of breast cancer. Identification of compounds that modulate ERRα signaling may elucidate environmental factors associated with these diseases. Therefore, we developed stable cell lines containing an intact ERRα signaling pathway, with and without the coactivator PGC-1α, to use as high-throughput screening tools to detect ERRα modulators. The lentiviral PGC-1α expression constructs and ERRα multiple hormone response element (MHRE) reporters were introduced into HEK293T cells that express endogenous ERRα. A cell line expressing the reporter alone was designated “ERR.” A second cell line expressing both reporter and PGC-1α was named “PGC/ERR.” Initial screenings of the Library of Pharmacol. Active Compounds (LOPAC) identified 33 ERR and 22 PGC/ERR agonists, and 54 ERR and 15 PGC/ERR antagonists. Several potent ERRα agonists were dietary plant compounds (e.g., genistein). In conclusion, these cell lines are suitable for high-throughput screens to identify environmental chems. affecting metabolic pathways and breast cancer progression.

SLAS Discovery published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C14H14N2O2, Synthetic Route of 330161-87-0.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Han, Aishan published the artcilePhosphate-affinity electrophoresis on a microchip for determination of protein kinase activity, Formula: C19H21N3O3S, the publication is Electrophoresis (2009), 30(20), 3507-3513, database is CAplus and MEDLINE.

We describe microchip-based phosphate-affinity electrophoresis (μPAE) for separation of peptides aimed at determination of kinase activity. The μPAE exploits two recently published technologies: autonomous sample injection for PDMS microchips and a phosphate-specific affinity ligand, Phos-tag. We prepared a fluorescently labeled substrate peptide, specific to human c-Src, and its phosphorylated form. We synthesized a Phos-tag-poly(dimethylacrylamide) conjugate. The conjugate and the sample solutions were autonomously injected into a PDMS-glass hybrid microchip. The two solutions were contacted together in the microchannel. When the peptides were electrophoresed into the Phos-tag-poly(dimethylacrylamide) region, the phosphorylated peptide was specifically trapped, and separated from the nonphosphorylated peptide in 10 s. The results were quantified by the areas of the fluorescence peaks. The calibration plot obtained with standard samples showed an excellent linearity and a LOD of 0.9% phosphorylated peptide among the total peptides. For c-Src-reacted samples, the results from the μPAE were in good agreement with those from matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The μPAE was also successful in the presence of inhibitors for c-Src. The measured 50% inhibitory concentration values for staurosporine, PP2, and SU6656 were in good agreement with the literature values.

Electrophoresis published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C19H21N3O3S, Formula: C19H21N3O3S.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Baek, Hye Suk published the artcileKMU-1170, a novel multi-protein kinase inhibitor, suppresses inflammatory signal transduction in THP-1 cells and human osteoarthritic fibroblast-like synoviocytes by suppressing activation of NF-κB and NLRP3 inflammasome signaling pathway, Recommanded Product: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one, the publication is International Journal of Molecular Sciences (2021), 22(3), 1194, database is CAplus and MEDLINE.

Protein kinases regulate protein phosphorylation, which are involved in fundamental cellular processes such as inflammatory response. In this study, we discovered a novel multi-protein kinase inhibitor, KMU-1170, a derivative of indolin-2-one, and investigated the mechanisms of its inflammation-inhibiting signaling in both THP-1 cells and human osteoarthritic fibroblast-like synoviocytes (FLS). We demonstrated that in THP-1 cells, KMU-1170 inhibited lipopolysaccharide (LPS)-induced upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and, furthermore, suppressed LPS-induced phosphorylation of transforming growth factor-β-activated kinase 1, JNK, ERK, inhibitor of NF-κB kinase α/β (IKKα/β), and NF-κB p65 as well as nuclear translocation of NF-κB p65. Moreover, KMU-1170 suppressed LPS-induced upregulation of proinflammatory cytokines such as IL-1β, TNF-α, and IL-6, and, notably, inhibited LPS-induced upregulation of the NLRP3 inflammasome in THP-1 cells. Importantly, KMU-1170 attenuated LPS-mediated inflammatory responses in human osteoarthritic FLS, such as the upregulation of IL-1β, TNF-α, IL-6, iNOS, and COX-2 and the phosphorylation of IKKα/β and NF-κB p65. Collectively, these results suggest that KMU-1170 inhibits inflammatory signal transduction and could be developed as a potential anti-inflammatory agent.

International Journal of Molecular Sciences published new progress about 837392-64-0. 837392-64-0 belongs to indole-building-block, auxiliary class Indoline,Boronic acid and ester,Amide,Boronate Esters, name is 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one, and the molecular formula is C14H18BNO3, Recommanded Product: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Kuroda, Yoshiyuki published the artcileRegulation of hyaluronan production by β2 adrenergic receptor signaling, Related Products of indole-building-block, the publication is Biochemical and Biophysical Research Communications (2021), 50-55, database is CAplus and MEDLINE.

Hyaluronan (HA), the main component of the extracellular matrix, is involved in tissue elasticity and cell scaffolding, and in progression of conditions such as cancer, inflammation and wound healing. Signaling by G protein coupled receptor (GPCR) activation increases expression of hyaluronan synthase (HAS) and HA production The β2 adrenergic receptor (β2AR) is a catecholamine-liganded GPCR that is involved in cancer progression and wound healing. Since HA and β2AR are involved in a common pathol., we investigated whether β2AR signaling regulates HA production After stimulating β2AR-expressing cells with a β agonist, the amount of HA in the culture medium was measured and HAS expression was examined by real-time PCR. A variety of signaling mol. inhibitors were used to identify signaling pathways that alter HAS expression.β2AR activation increased HA production and enhanced HAS2 expression. The increase in HAS2 expression by β2AR activation occurred via the Gs – adenylyl cyclase – PKA – CREB signal transduction pathway. Downstream signal transduction by β2AR activation increased HA production by enhancing transcription of the HAS2 gene. This study suggests that β2AR is a GPCR that regulates HA production, and that stimulation with a catecholamine (β2 agonist) can regulate HA productionβ2AR may function through regulation of HA production in cancer progression and wound healing.

Biochemical and Biophysical Research Communications published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C19H21N3O3S, Related Products of indole-building-block.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Niggenaber, Janina published the artcileComplex Crystal Structures of EGFR with Third-Generation Kinase Inhibitors and Simultaneously Bound Allosteric Ligands, Synthetic Route of 1942114-09-1, the publication is ACS Medicinal Chemistry Letters (2020), 11(12), 2484-2490, database is CAplus and MEDLINE.

Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) and currently the gold-standard for the treatment of patients suffering from non-small cell lung cancer (NSCLC) harboring T790M-mutated epidermal growth factor receptor (EGFR). The outcome of the treatment, however, is limited by the emergence of the C797S resistance mutation. Allosteric inhibitors have a different mode of action and were developed to overcome this limitation. However, most of these innovative mols. are not effective as a single agent. Recently, mutated EGFR was successfully addressed with osimertinib combined with the allosteric inhibitor JBJ-04-125-02, but surprisingly, structural insights into their binding mode were lacking. Here, we present the first complex crystal structures of mutant EGFR in complex with third-generation inhibitors such as osimertinib and mavelertinib in the presence of simultaneously bound allosteric inhibitors. These structures highlight the possibility of further combinations targeting EGFR and lay the foundation for hybrid inhibitors as next-generation TKIs.

ACS Medicinal Chemistry Letters published new progress about 1942114-09-1. 1942114-09-1 belongs to indole-building-block, auxiliary class Indoline,Thiazole,Fluoride,Amine,Benzene,Amide,Alcohol,Protein Tyrosine Kinase/RTK, name is 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, and the molecular formula is C19H14FN3O3S, Synthetic Route of 1942114-09-1.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Wittlinger, Florian published the artcileDesign of a “Two-in-One” Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites, Computed Properties of 1942114-09-1, the publication is Journal of Medicinal Chemistry (2022), 65(2), 1370-1383, database is CAplus and MEDLINE.

Inhibitors targeting the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harboring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations has motivated the development of successive generations of inhibitors that bind in the ATP site. The third-generation agent osimertinib is now a first-line treatment for this disease. Recently, allosteric inhibitors have been developed to overcome drug-resistant mutations that confer a resistance to osimertinib. Here, we present the structure-guided design and synthesis of a mutant-selective lead compound, which consists of a pyridinyl imidazole-fused benzylisoindolinedione scaffold that simultaneously occupies the orthosteric and allosteric sites. The compound potently inhibits enzymic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with a significantly lower activity for wild-type EGFR (47 nM). Addnl., this compound achieves modest cetuximab-independent and mutant-selective cellular efficacies on the L858R (1.2 μM) and L858R/T790M (4.4 μM) variants.

Journal of Medicinal Chemistry published new progress about 1942114-09-1. 1942114-09-1 belongs to indole-building-block, auxiliary class Indoline,Thiazole,Fluoride,Amine,Benzene,Amide,Alcohol,Protein Tyrosine Kinase/RTK, name is 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, and the molecular formula is C9H6N2O2, Computed Properties of 1942114-09-1.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Park, Hwa-Jeong published the artcileUp-regulated fibronectin in 3D culture facilitates spreading of triple negative breast cancer cells on 2D through integrin β-5 and Src, COA of Formula: C19H21N3O3S, the publication is Scientific Reports (2019), 9(1), 19950, database is CAplus and MEDLINE.

Using MDA-MB-231 cells as a model of triple neg. breast cancer (TNBC) and its metastatic sub-cell lines that preferentially metastasize to lung, bone or brain, we found that the mRNA and protein levels of fibronectin (FN) are increased in MDA-MB-231 cells and its lung metastatic derivative, when cultivated in three-dimensional (3D) suspension cultures. The increase of FN expression in 3D was dependent on p38 mitogen-activated protein kinase (MAPK) because it was prevented by treatment of cells with SB203580, an inhibitor of p38MAPK. The up-regulated FN was converted into fibrils, and it enhanced cell spreading when cells cultured in 3D were transferred to two-dimensional (2D) culture. The arginine-glycine-aspartate (RGD) peptides and siRNAs targeting of integrin β-5 inhibited spreading of cells regardless of the presence of FN on 2D culture dishes. In addition, the levels of phosphorylated Src were found to be increased in 3D and the treatment of cells with SU6656, an inhibitor of Src, decreased the rate of cell spreading on FN. Collectively, these studies demonstrate that increased cellular FN in 3D suspension culture facilitates cancer cell attachment and spreading via integrin β-5 and Src, suggesting that the increased FN promotes initial attachment of cancer cells to secondary organs after circulation during metastasis.

Scientific Reports published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C19H21N3O3S, COA of Formula: C19H21N3O3S.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Korbee, Cornelis J. published the artcileCombined chemical genetics and data-driven bioinformatics approach identifies receptor tyrosine kinase inhibitors as host-directed antimicrobials, Application of SU6656, the publication is Nature Communications (2018), 9(1), 1-14, database is CAplus and MEDLINE.

Antibiotic resistance poses rapidly increasing global problems in combating multidrug-resistant (MDR) infectious diseases like MDR tuberculosis, prompting for novel approaches including host-directed therapies (HDT). Intracellular pathogens like Salmonellae and Mycobacterium tuberculosis (Mtb) exploit host pathways to survive. Only very few HDT compounds targeting host pathways are currently known. In a library of pharmacol. active compounds (LOPAC)-based drug-repurposing screen, we identify multiple compounds, which target receptor tyrosine kinases (RTKs) and inhibit intracellular Mtb and Salmonellae more potently than currently known HDT compounds By developing a data-driven in silico model based on confirmed targets from public databases, we successfully predict addnl. efficacious HDT compounds These compounds target host RTK signaling and inhibit intracellular (MDR) Mtb. A complementary human kinome siRNA screen independently confirms the role of RTK signaling and kinases (BLK, ABL1, and NTRK1) in host control of Mtb. These approaches validate RTK signaling as a drugable host pathway for HDT against intracellular bacteria.

Nature Communications published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C19H21N3O3S, Application of SU6656.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Zhou, Tao-tao published the artcileTyrosine kinase inhibitory activity of dehydroabietylamine derivatives tested by homogeneous time-resolved fluorescence based high throughput screening model, Recommanded Product: SU6656, the publication is Zhongguo Tianran Yaowu (2013), 11(5), 506-513, database is CAplus.

Protein tyrosine kinases (PTKs) are attractive targets in searching for therapeutic agents against many diseases. In this study, a series of dehydroabietylamine derivatives were first determined to show PTK inhibitory activity using a high-throughput screening (HTS) method based on homogeneous time-resolved fluorescence (HTRF) technol. The structure-activity relationships of the dehydroabietylamine derivatives were established, and it was found that the compounds with a nitrogen-containing side chain had better inhibitory activity. Further studies showed that the compounds substituted with halogen in the Ph ring resulted in higher inhibitory activity on the epidermal growth factor receptor (EGFR), and can be a guide to modify the structure of dehydroabietylamine derivatives Dehydroabietylamine derivatives might be a new class of multi-targeted and effective PTK inhibitors with structure modifications.

Zhongguo Tianran Yaowu published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C18H26ClN3O, Recommanded Product: SU6656.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles