Tag: M.W=350-400

Zhao, Peng published the artcileCrystal structure of EGFR T790M/C797S/V948R in complex with EAI045, Recommanded Product: 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, the publication is Biochemical and Biophysical Research Communications (2018), 502(3), 332-337, database is CAplus and MEDLINE.

Lung cancer is the leading cause of cancer deaths. Epidermal growth factor receptor (EGFR) kinase domain mutations are a common cause of non-small cell lung cancers (NSCLCs), a major subtype of lung cancers. Patients harboring most of these mutations respond well to the anti-EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib initially, but soon develop resistance to them in about half of the cases due to the emergence of the gatekeeper mutation T790M. The third-generation TKIs such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to the EGFR kinase through Cys 797, but ultimately lose their efficacy upon emergence of the C797S mutation that abolishes the covalent bonding. Therefore to develop new TKIs to overcome EGFR drug-resistant mutants harboring T790M/C797S is urgently demanded. EAI001 and EAI045 are a new type of EGFR TKIs that bind to EGFR reversibly and not relying on Cys 797. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by EGFR L858R/T790M and L858R/T790M/C797S. Here we report the crystal structure of EGFR T790M/C797S/V948R in complex with EAI045, and compare it to EGFR T790M/V948R in complex with EAI001. The complex structure reveals why EAI045 binds tighter to EGFR than does EAI001, and why EAI001 and EAI045 prefer binding to EGFR T790M. The knowledge may facilitate future drug development studies targeting this very important cancer target.

Biochemical and Biophysical Research Communications 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 C14H22O2, Recommanded Product: 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide.

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

Okubo, Ayaka published the artcileNAD(P)H dehydrogenase, quinone 1 (NQO1), protects melanin-producing cells from cytotoxicity of rhododendrol, Safety of 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, the publication is Pigment Cell & Melanoma Research (2016), 29(3), 309-316, database is CAplus and MEDLINE.

Summary : Rhododendrol (RD) is a potent tyrosinase inhibitor that is metabolized to RD-quinone by tyrosinase, which may underlie the cytotoxicity of RD and leukoderma of the skin that may result. We have examined how forced expression of the NAD(P)H quinone dehydrogenase, quinone 1 (NQO1), a major quinone-reducing enzyme in cytosol, affects the survival of RD-treated cells. We found that treatment of the mouse melanoma cell line B16BL6 or normal human melanocytes with carnosic acid, a transcriptional inducer of the NQO1 gene, notably suppressed the cell killing effect of RD. This effect was mostly abolished by ES936, a highly specific NQO1 inhibitor. Moreover, conditional overexpression of the human NQO1 transgene in B16BL6 led to an expression-dependent increase of cell survival after RD treatment. Our results suggest that NQO1 attenuates the cytotoxicity of RD and/or its metabolites.

Pigment Cell & Melanoma Research published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C18H16N2O6, Safety of 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione.

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

Beall, Howard D. published the artcileIndolequinone Antitumor Agents: Correlation between Quinone Structure, Rate of Metabolism by Recombinant Human NAD(P)H:Quinone Oxidoreductase, and in Vitro Cytotoxicity, Category: indole-building-block, the publication is Journal of Medicinal Chemistry (1998), 41(24), 4755-4766, database is CAplus and MEDLINE.

A series of indolequinones bearing various functional groups has been synthesized, and the effects of substituents on the metabolism of the quinones by recombinant human NAD(P)H:quinone oxidoreductase (NQO1) were studied. Thus 5-methoxyindolequinones were prepared by the Nenitzescu reaction, followed by functional group interconversions. The methoxy group was subsequently displaced by amine nucleophiles to give a series of amine-substituted quinones. Metabolism of the quinones by NQO1 revealed that, in general, compounds with electron-withdrawing groups at the indole 3-position were among the best substrates, whereas those with amine groups at the 5-position were poor substrates. Compounds with a leaving group at the 3-indolyl Me position generally inactivated the enzyme. The toxicity toward non-small-cell lung cancer cells with either high NQO1 activity (H460) or no detectable activity (H596) was also studied in representative quinones. Compounds which were good substrates for NQO1 showed the highest selectivity between the two cell lines.

Journal of Medicinal Chemistry published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C18H16N2O6, Category: 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

Yeyeodu, Susan T. published the artcileA rapid, inexpensive high throughput screen method for neurite outgrowth, SDS of cas: 330161-87-0, the publication is Current Chemical Genomics (2010), 74-83, database is CAplus and MEDLINE.

Neurite outgrowth assays are the most common phenotypic screen to assess chem. effects on neuronal cells. Current automated assays involve expensive equipment, lengthy sample preparation and handling, costly reagents and slow rates of data acquisition and anal. We have developed a high throughput screen (HTS) for neurite outgrowth using a robust neuronal cell model coupled to fast and inexpensive visualization methods, reduced data volume and rapid data anal. Neuroscreen-1 (NS-1) cell, a subclone of PC12, possessing rapid growth and enhanced sensitivity to NGF was used as a model neuron. This method reduces preparation time by using cells expressing GFP or native cells stained with HCS CellMask Red in a multiplexed 30 min fixation and staining step. A 2 × 2 camera binning process reduced both image data files and anal. times by 75% and 60% resp., compared to current protocols. In addition, eliminating autofocus steps during montage generation reduced data collection time. Pharmacol. profiles for stimulation and inhibition of neurite outgrowth by NGF and SU6656 were comparable to current standard method utilizing immunofluorescence detection of tubulin. Potentiation of NGF-induced neurite outgrowth by members of a 1,120-member Prestwick compound library as assayed using this method identified six mols., including etoposide, isoflupredone acetate, fludrocortisone acetate, thioguanosine, oxyphenbutazone and gibberellic acid, that more than doubled the neurite mass primed by 2 ng/mL NGF. This simple procedure represents an important routine approach in high throughput screening of large chem. libraries using the neurite outgrowth phenotype as a measure of the effects of chem. mols. on neuronal cells.

Current Chemical Genomics 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 C10H18BNO2, SDS of cas: 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

Friedman, Adam A. published the artcileFeasibility of Ultra-High-Throughput Functional Screening of Melanoma Biopsies for Discovery of Novel Cancer Drug Combinations, Recommanded Product: SU6656, the publication is Clinical Cancer Research (2017), 23(16), 4680-4692, database is CAplus and MEDLINE.

Purpose: Successful development of targeted therapy combinations for cancer patients depends on first discovering such combinations in predictive preclin. models. Stable cell lines and mouse xenograft models can have genetic and phenotypic drift and may take too long to generate to be useful as a personalized medicine tool. Exptl. Design: To overcome these limitations, we have used a platform of ultra-high-throughput functional screening of primary biopsies preserving both cancer and stroma cell populations from melanoma patients to nominate such novel combinations from a library of thousands of drug combinations in a patient-specific manner within days of biopsy. In parallel, patient-derived xenograft (PDX) mouse models were created and novel combinations tested for their ability to shrink matched PDXs. Results: The screening method identifies specific drug combinations in tumor cells with patterns that are distinct from those obtained from stable cell lines. Screening results were highly specific to individual patients. For patients with matched PDX models, we confirmed that individualized novel targeted therapy combinations could inhibit tumor growth. In particular, a combination of multi-kinase and PI3K/Akt inhibitors was effective in some BRAF-wild-type melanomas, and the addition of cediranib to the BRAF inhibitor PLX4720 was effective in a PDX model with BRAF mutation. Conclusions: This proof-of-concept study demonstrates the feasibility of using primary biopsies directly for combinatorial drug discovery, complementing stable cell lines and xenografts, but with much greater speed and efficiency. This process could potentially be used in a clin. setting to rapidly identify therapeutic strategies for individual patients. Clin Cancer Res; 23(16); 4680-92. ©2017 AACR.

Clinical Cancer Research 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

Liu, Xiu-Fen published the artcileAntitumor Effects of Immunotoxins Are Enhanced by Lowering HCK or Treatment with Src Kinase Inhibitors, Product Details of C19H21N3O3S, the publication is Molecular Cancer Therapeutics (2014), 13(1), 82-89, database is CAplus and MEDLINE.

Recombinant immunotoxins (RIT) are agents being developed for cancer treatment. They are composed of an Fv that binds to a cancer cell, fused to a 38-kDa fragment of Pseudomonas exotoxin A. SS1P is a RIT that targets mesothelin, a protein expressed on mesothelioma as well as pancreatic, ovarian, lung, and other cancers. Because the protein tyrosine kinase family regulates a variety of cellular processes and pathways, we hypothesized that tyrosine kinases might regulate susceptibility to immunotoxin killing. To investigate their role, we used siRNAs to lower the level of expression of the 88 known tyrosine kinases. We identified five tyrosine kinases, INSR, HCK, SRC, PDGFRβ, and BMX that enhance the activity of SS1P when their level of expression is lowered by siRNAs. We further investigated the Src family member HCK in this study. Knocking down of SRC slightly increased SS1P killing in A431/H9 cells, but knocking down HCK substantially enhanced killing by SS1P. We investigated the mechanism of enhancement and found that HCK knockdown enhanced SS1P cleavage by furin and lowered levels of Mcl-1 and raised Bax. We then found that Src inhibitors mimic the stimulatory effect of HCK knockdown; both SU6656 and SKI-606 (bosutinib) enhanced immunotoxin killing of mesothelin-expressing cells by SS1P and CD22-expressing cells by HA22 (moxetumomab pasudotox). SU6656 also enhanced the antitumor effects of SS1P and HA22 in mouse xenograft tumor models. Our data suggest that the combination of immunotoxin with tyrosine kinase inhibitors may be an effective way to treat some cancers. Mol Cancer Ther; 13(1); 82-89. ©2013 AACR.

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

Chu, Zixuan published the artcileDevelopment and Validation of an LC-MS/MS Method for Quantitative Determination of EAI045, A Novel EGFR Inhibitor, in Rat Plasma, Category: indole-building-block, the publication is Current Pharmaceutical Analysis (2020), 16(3), 273-279, database is CAplus.

EAI045 is the fourth-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), which can overcome acquired resistance to the third-generation EGFR TKIs and is the first allosteric inhibitor that targets T790M and C797S EGFR mutants. A rapid and sensitive LC-MS/MS method was established and validated for the quantification of EAI045 in rat plasma. Chromatog. separation was carried out at 25°C on a Hypersil GOLD C18 column (50 mm x 2.1 mm, 3μm) and eluted on a gradient mobile phase of water (containing 0.1% formic acid) and acetonitrile at a flow rate of 0.5 mL/min. The mass spectrometer was operated in the pos. ESI mode and selected reaction monitoring mode. The assay was validated over a concentration range of 1.0 – 1000 ng/mL for EAI045 with a lower limit of quantification (LLOQ) of 1.0 ng/mL. The intra- and inter-batch accuracy for the EAI045 ranged from 92.25% to 97.18% and 95.94% to 102.69%, and the intra- and inter-batch precision for the EAI045 ranged from 1.41% to 4.57% and 5.18% to 6.37%, resp. The extraction recovery, matrix effect and stability met all requirements of the guidelines for bioanal. method validation. The rapid and sensitive LC-MS/MS method was successfully applied in a pharmacokinetic study of EAI045 following oral administration (5 mg/kg) to rats.

Current Pharmaceutical Analysis 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, Category: 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

Wu, Xiuli published the artcileValidated LC method for the enantiomeric separation of EAI045 on chiral stationary phase, Product Details of C19H14FN3O3S, the publication is Journal of Chromatographic Science (2020), 58(6), 562-568, database is CAplus and MEDLINE.

A simple and accurate chiral liquid chromatog. method was developed for enantiomeric resolution and determination of 2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-(1,3-thiazol-2-yl)acetamide (EAI045). The enantiomers of EAI045 were baseline resolved on a Chiralpak AD-H (250 mm x 4.6 mm, 5μm) column using a mobile phase system containing n-hexane: 2-propanol (75: 25 volume/volume) at a flow rate of 1 mL min-1 at 30°C. The eluted analytes were subsequently detected with an UV detector at 254 nm. The effects of organic modifiers and temperature on the enantioselectivity and resolution of the enantiomers were evaluated. The calibration curves were plotted within the concentration range between 2 and 600μg mL-1 (n = 11), and recoveries between 98.74% and 101.52% were obtained, with relative standard deviation < 1.4%. The limit of detection and limit of quantitation for R-enantiomer were 0.94 and 3.07μg mL-1 and for S-enantiomer were 0.86 and 2.84μg mL-1, resp. The validated method was found to be suitable for enantiomeric separation and sufficiently accurate for the determination of enantiomeric purity of EAI045 in bulk drugs.

Journal of Chromatographic Science 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 C11H10ClNO, Product Details of C19H14FN3O3S.

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

Qin, Bo published the artcileSrc family kinases (SFK) mediate angiotensin II-induced myosin light chain phosphorylation and hypertension, Recommanded Product: SU6656, the publication is PLoS One (2015), 10(5), e0127891/1-e0127891/7, database is CAplus and MEDLINE.

Angiotensin (Ang) II is the major bioactive peptide of the renin-angiotensin system (RAS); it contributes to the pathogenesis of hypertension by inducing vascular contraction and adverse remodeling, thus elevated peripheral resistance. Ang II also activates Src family kinases (SFK) in the vascular system, which has been implicated in cell proliferation and migration. However, the role of SFK in Ang II-induced hypertension is largely unknown. In this study, we found that administration of a SFK inhibitor SU6656 markedly lowered the level of systemic BP in Ang II-treated mice, which was associated with an attenuated phosphorylation of the smooth-muscle myosin-light-chain (MLC) in the mesenteric resistant arteries. In the cultured human coronary artery smooth muscle cells (SMCs), pretreatment with SU6656 blocked Ang II-induced MLC phosphorylation and contraction. These results for the first time demonstrate that SFK directly regulate vascular contractile machinery to influence BP. Thus our study provides an addnl. mechanistic link between Ang II and vasoconstriction via SFK-enhanced MLC phosphorylation in SMCs, and suggests that targeted inhibition of Src may provide a new therapeutic opportunity in the treatment of hypertension.

PLoS One 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

Zhang, Chenghu published the artcileCoupling of Integrin α5 to Annexin A2 by Flow Drives Endothelial Activation, Application of SU6656, the publication is Circulation Research (2020), 127(8), 1074-1090, database is CAplus and MEDLINE.

RATIONALE: Atherosclerosis preferentially occurs at specific sites of the vasculature where endothelial cells (ECs) are exposed to disturbed blood flow. Translocation of integrin α5 to lipid rafts promotes integrin activation and ligation, which is critical for oscillatory shear stress (OSS)-induced EC activation. However, the underlying mechanism of OSS promoted integrin α5 lipid raft translocation has remained largely unknown. OBJECTIVE: The objective of this study was to specify the mechanotransduction mechanism of OSS-induced integrin α5 translocation and subsequent EC activation. METHODS AND RESULTS: Mass spectrometry studies identified endothelial ANXA2 (annexin A2) as a potential carrier allowing integrin α5β1 to traffic in response to OSS. Interference by siRNA of AnxA2 in ECs greatly decreased OSS-induced integrin α5β1 translocation to lipid rafts, EC activation, and monocyte adhesion. Pharmacol. and genetic inhibition of PTP1B (protein tyrosine phosphatase 1B) blunted OSS-induced integrin α5β1 activation, which is dependent on Piezo1-mediated calcium influx in ECs. Furthermore, ANXA2 was identified as a direct substrate of activated PTP1B by mass spectrometry. Using bioluminescence resonance energy transfer assay, PTP1B-dephosphorylated ANXA2 at Y24 was found to lead to conformational freedom of the C-terminal core domain from the N-terminal domain of ANXA2. Immunoprecipitation assays showed that this unmasked ANXA2-C-terminal core domain specifically binds to an integrin α5 nonconserved cytoplasmic domain but not β1. Importantly, ectopic lentiviral overexpression of an ANXA2^Y24F mutant increased and shRNA against Ptp1B decreased integrin α5β1 ligation, inflammatory signaling, and progression of plaques at atheroprone sites in apolipoprotein E (ApoE)^-/- mice. However, the antiatherosclerotic effect of Ptp1B shRNA was abolished in AnxA2^-/-ApoE^-/- mice. CONCLUSIONS: Our data elucidate a novel endothelial mechanotransduction mol. mechanism linking atheroprone flow and activation of integrin α5β1, thereby identifying a class of potential therapeutic targets for atherosclerosis.

Circulation Research 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 C16H12O, 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