Tag: M.W=350-400

Kilic, Zuhal published the artcileEvaluation of new indole and bromoindole derivatives as pp60^c-Src tyrosine kinase inhibitors, Application of SU6656, the publication is Chemical Biology & Drug Design (2009), 74(4), 397-404, database is CAplus and MEDLINE.

A series of N-benzyl-indole-3-imine-, amine derivatives and their 5-bromo congeners were synthesized and their biol. activity were evaluated against the pp60^c-Src tyrosine kinase target. To afford the imine derivatives, aldehydes were reacted with substituted benzylamines and the corresponding amine derivatives were obtained by NaBH₄ reduction of these imines. Except insoluble N-benzyl-indole-3-imine derivatives, all the derivatives showed some activity against the kinase target. Screening of these compounds for their biol. activity revealed that among N-benzylindole derivatives, those bearing 5-bromo substitution have the enhanced potency, where the amine derivatives were more active than imines.

Chemical Biology & Drug Design 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

Riffell, Jenna L. published the artcileCaspase-3-Dependent Mitotic Checkpoint Inactivation by the Small-Molecule Inducers of Mitotic Slippage SU6656 and Geraldol, Product Details of C19H21N3O3S, the publication is Molecular Cancer Therapeutics (2011), 10(5), 839-849, database is CAplus and MEDLINE.

Microtubule-targeting cancer drugs such as paclitaxel block cell-cycle progression at mitosis by prolonged activation of the mitotic checkpoint. Cells can spontaneously escape mitotic arrest and enter interphase without chromosome segregation by a process termed mitotic slippage that involves the degradation of cyclin B1 without mitotic checkpoint inactivation. Inducing mitotic slippage with chems. causes cells to die after multiple rounds of DNA replication without cell division, which may enhance the antitumor activity of microtubule-targeting drugs. Here, we explore pathways leading to mitotic slippage by using SU6656 and geraldol, two recently identified chem. inducers of mitotic slippage. Mitotic slippage induced by SU6656 or geraldol was blocked by the proteasome inhibitor MG-132 and involved proteasome-dependent degradation of cyclin B1 and the mitotic checkpoint proteins budding uninhibited by benzimidazole related 1 (BubR1) and cell division cycle 20 (Cdc20) in T98G cells. Mitotic slippage and the degradation of BubR1 and Cdc20 were also inhibited by the caspase-3 and -7 inhibitor DEVD-CHO. MCF-7 cells lacking caspase-3 expression could not degrade BubR1 or undergo mitotic slippage in response to SU6656 or geraldol. Introduction of caspase-3 completely restored the ability of MCF-7 cells to degrade BubR1 and undergo mitotic slippage. However, lack of expression of caspase-3 did not affect cell death after exposure to paclitaxel, with or without mitotic slippage induction. The requirement for caspase-3 for chem. induced mitotic slippage reveals a new mechanism for mitotic exit and a link between mitosis and apoptosis that has implications for the outcome of cancer chemotherapy. Mol Cancer Ther; 10(5); 839-49.

Molecular Cancer Therapeutics 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, Product Details of 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

Yu, Ah-Ran published the artcileAlpha-naphthoflavone induces apoptosis through endoplasmic reticulum stress via c-Src-, ROS-, MAPKs-, and arylhydrocarbon receptor-dependent pathways in HT22 hippocampal neuronal cells, Quality Control of 330161-87-0, the publication is NeuroToxicology (2019), 39-51, database is CAplus and MEDLINE.

α-Naphthoflavone (αNF) is a prototype flavone, also known as a modulator of aryl hydrocarbon receptor (AhR). In the present study, we investigated the mol. mechanisms of αNF-induced cytotoxic effects in HT22 mouse hippocampal neuronal cells. αNF induced apoptotic cell death via activation of caspase-12 and -3 and increased expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP). Inhibition of ER stress by treatment with the ER stress inhibitor, salubrinal, or by CHOP siRNA transfection reduced αNF-induced cell death. αNF activated mitogen-activated protein kinases (MAPKs), such as p38, JNK, and ERK, and inhibition of MAPKs reduced αNF-induced CHOP expression and cell death. αNF also induced accumulation of reactive oxygen species (ROS) and an antioxidant, N-acetylcysteine, reduced αNF-induced MAPK phosphorylation, CHOP expression, and cell death. Furthermore, αNF activated c-Src kinase, and inhibition of c-Src by a kinase inhibitor, SU6656, or siRNA transfection reduced αNF-induced ROS accumulation, MAPK activation, CHOP expression, and cell death. Inhibition of AhR by an AhR antagonist, CH223191, and siRNA transfection of AhR and AhR nuclear translocator reduced αNF-induced AhR-responsive luciferase activity, CHOP expression, and cell death. Finally, we found that inhibition of c-Src and MAPKs reduced αNF-induced transcriptional activity of AhR. Taken together, these findings suggest that αNF induces apoptosis through ER stress via c-Src-, ROS-, MAPKs-, and AhR-dependent pathways in HT22 cells.

NeuroToxicology 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 C15H20BNO5, Quality Control 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

Zhao, Yan published the artcileRevisiting the molecular mechanism of acquired resistance to reversible tyrosine kinase inhibitors caused by EGFR gatekeeper T790M mutation in non-small-cell lung cancer, Related Products of indole-building-block, the publication is Medicinal Chemistry Research (2018), 27(9), 2160-2170, database is CAplus.

A variety of tyrosine kinase inhibitors (TKIs) have been developed to target human epidermal growth factor receptor (EGFR) for non-small-cell lung cancer (NSCLC) therapy. However, many patients treated with first-line TKIs are clin. observed to eventually establish a gatekeeper T790M mutation in EGFR active site, which plays a primary role in development of acquired resistance to TKIs. Here, we attempted to investigate the intermol. interactions of wild-type EGFR (EGFRWT) and its T790M mutant (EGFRT790M) with a number of culled reversible EGFR TKIs, paying attention to the structural and energetic response of inhibitor ligands to the mutation. A TKI panel consisting of 9 sophisticated EGFR inhibitors was manually culled, and an integration of structural modeling, virtual mutagenesis, quantum mechanics/mol. mechanics anal. and binding assay was performed to systematically examine the binding of these inhibitors to both wild-type and mutant EGFR. T790M-introduced steric hindrance plays a primary role in the acquired resistance to WT-selective inhibitors, whereas the mutation is observed to form addnl. noncovalent forces with WT-sparing inhibitors. Structural anal. reveals that the steric hindrance generally induces a conformational change of WT-selective inhibitors in EGFR active site, while the weak noncovalent forces have only a moderate effect on the binding mode of WT-sparing inhibitors. EAI045, the first fourth-generation EGFR inhibitor, exhibits a moderate affinity to EGFR and possesses an exquisite selectivity for wild type over mutant kinase (�-fold). This is expected if considering that the EAI045 is an allosteric inhibitor, which does not need to directly compete with ATP, and high affinity and selectivity are therefore not required for the inhibitor.

Medicinal Chemistry Research 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 C9H9BN2O3, 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

Arang, Nadia published the artcileIdentifying host regulators and inhibitors of liver stage malaria infection using kinase activity profiles, Recommanded Product: SU6656, the publication is Nature Communications (2017), 8(1), 1-9, database is CAplus and MEDLINE.

Plasmodium parasites have extensive needs from their host hepatocytes during the obligate liver stage of infection, yet there remains sparse knowledge of specific host regulators. Here we assess 34 host-targeted kinase inhibitors for their capacity to eliminate Plasmodium yoelii-infected hepatocytes. Using pre-existing activity profiles of each inhibitor, we generate a predictive computational model that identifies host kinases, which facilitate Plasmodium yoelii liver stage infection. We predict 47 kinases, including novel and previously described kinases that impact infection. The impact of a subset of kinases is exptl. validated, including Receptor Tyrosine Kinases, members of the MAP Kinase cascade, and WEE1. Our approach also predicts host-targeted kinase inhibitors of infection, including compounds already used in humans. Three of these compounds, VX-680, Roscovitine and Sunitinib, each eliminate >85% of infection. Our approach is well-suited to uncover key host determinants of infection in difficult model systems, including field-isolated parasites and/or emerging pathogens.

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, 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

Ross, Fiona A. published the artcileMechanisms of Paradoxical Activation of AMPK by the Kinase Inhibitors SU6656 and Sorafenib, Safety of SU6656, the publication is Cell Chemical Biology (2017), 24(7), 813-824.e4, database is CAplus and MEDLINE.

SU6656, a Src kinase inhibitor, was reported to increase fat oxidation and reduce body weight in mice, with proposed mechanisms involving AMP-activated protein kinase (AMPK) activation via inhibition of phosphorylation of either LKB1 or AMPK by the Src kinase, Fyn. However, we report that AMPK activation by SU6656 is independent of Src kinases or tyrosine phosphorylation of LKB1 or AMPK and is not due to decreased cellular energy status or binding at the ADaM site on AMPK. SU6656 is a potent AMPK inhibitor, yet binding at the catalytic site paradoxically promotes phosphorylation of Thr172 by LKB1. This would enhance phosphorylation of downstream targets provided the lifetime of Thr172 phosphorylation was sufficient to allow dissociation of the inhibitor and subsequent catalysis prior to its dephosphorylation. By contrast, sorafenib, a kinase inhibitor in clin. use, activates AMPK indirectly by inhibiting mitochondrial metabolism and increasing cellular AMP:ADP and/or ADP:ATP ratios.

Cell Chemical Biology 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, Safety 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

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

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

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