Tag: M.W=350-400

Apsel, Beth published the artcileTargeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases, Computed Properties of 1025707-92-9, the publication is Nature Chemical Biology (2008), 4(11), 691-699, database is CAplus and MEDLINE.

The clin. success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of mols. that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chem. synthesis, X-ray crystallog. and kinome-level biochem. profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these mols. is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that compound I blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These mols. demonstrate the feasibility of accessing a chem. space that intersects two families of oncogenes.

Nature Chemical Biology published new progress about 1025707-92-9. 1025707-92-9 belongs to indole-building-block, auxiliary class Indole,Boronic acid and ester,Amide,Aldehyde,Boronate Esters,Boronic Acids,Boronic acid and ester,, name is tert-Butyl 3-formyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate, and the molecular formula is C20H26BNO5, Computed Properties of 1025707-92-9.

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

Woudenberg-Vrenken, Titia E. published the artcileAnti-oxidants do not prevent bile acid-induced cell death in rat hepatocytes, Safety of SU6656, the publication is Liver International (2010), 30(10), 1511-1521, database is CAplus and MEDLINE.

Background: Bile acids, reactive oxygen species (ROS) and inflammatory cytokines are crucial regulators of cell death in acute and chronic liver diseases. The contribution of each factor to hepatocyte death, either apoptosis or necrosis, has not been clarified as yet. It has been suggested that the generation of oxidative stress by bile acids contributes to hepatocyte death during cholestasis and bile acid toxicity, although the beneficial role of ROS prevention in bile acid-mediated cell death is not fully understood. Aim: Study the effects of anti-oxidants in bile acid-induced cell death in vitro. Methods: Primary rat hepatocytes were exposed to the bile acids glycochenodeoxycholic acid (GCDCA) or taurolithocholic acid-3 sulfate in the absence or presence of ROS scavengers or anti-oxidants. Heme oxygenase (HO)-1 mRNA levels were analyzed by quant. polymerase chain reaction. Apoptosis was quantified by acridine orange staining and caspase-3 activity assay. Necrosis was detected by Sytox green staining. Results: Anti-oxidants do not attenuate bile acid-induced cell death. Furthermore, bile acid exposure does not enhance the mRNA expression of the oxidative stress-responsive gene HO-1. The Src-kinase inhibitor, SU6656, does reduce GCDCA-induced apoptosis and necrosis. Conclusions: In hepatocytes, bile acid-induced toxicity is not prevented by scavengers of oxidative stress. The beneficial effects observed in patients might be because of the contribution of ROS and cytokines rather than bile acid-mediated oxidative stress. However, the use of specific Src kinase inhibitors might be a useful tool to prevent bile acid-induced injury in liver diseases.

Liver International 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 C3H9ClOS, 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

Kiris, Erkan published the artcileSrc Family Kinase Inhibitors Antagonize the Toxicity of Multiple Serotypes of Botulinum Neurotoxin in Human Embryonic Stem Cell-Derived Motor Neurons, Recommanded Product: SU6656, the publication is Neurotoxicity Research (2015), 27(4), 384-398, database is CAplus and MEDLINE.

Botulinum neurotoxins (BoNTs), the causative agents of botulism, are potent inhibitors of neurotransmitter release from motor neurons. There are currently no drugs to treat BoNT intoxication after the onset of the disease symptoms. In this study, we explored how modulation of key host pathways affects the process of BoNT intoxication in human motor neurons, focusing on Src family kinase (SFK) signaling. Motor neurons derived from human embryonic stem (hES) cells were treated with a panel of SFK inhibitors and intoxicated with BoNT serotypes A, B, or E (which are responsible for >95 % of human botulism cases). Subsequently, it was found that bosutinib, dasatinib, KX2-391, PP1, PP2, Src inhibitor-1, and SU6656 significantly antagonized all three of the serotypes. Furthermore, the data indicated that the treatment of hES-derived motor neurons with multiple SFK inhibitors increased the antagonistic effect synergistically. Mechanistically, the small mols. appear to inhibit BoNTs by targeting host pathways necessary for intoxication and not by directly inhibiting the toxins’ proteolytic activity. Importantly, the identified inhibitors are all well-studied with some in clin. trials while others are FDA-approved drugs. Overall, this study emphasizes the importance of targeting host neuronal pathways, rather than the toxin’s enzymic components, to antagonize multiple BoNT serotypes in motor neurons.

Neurotoxicity 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

Chevalier, Clement published the artcileABL tyrosine kinase inhibition variable effects on the invasive properties of different triple negative breast cancer cell lines, COA of Formula: C19H21N3O3S, the publication is PLoS One (2015), 10(3), e0118854/1-e0118854/16, database is CAplus and MEDLINE.

The non-receptor tyrosine kinase ABL drives myeloid progenitor expansion in human chronic myeloid leukemia. ABL inhibition by the tyrosine kinase inhibitor nilotinib is a first-line treatment for this disease. Recently, ABL has also been implicated in the transforming properties of solid tumors, including triple neg. (TN) breast cancer. TN breast cancers are highly metastatic and several cell lines derived from these tumors display high invasive activity in vitro. This feature is associated with the activation of actin-rich membrane structures called invadopodia that promote extracellular matrix degradation Here, we investigated nilotinib effect on the invasive and migratory properties of different TN breast cancer cell lines. Nilotinib decreased both matrix degradation and invasion in the TN breast cancer cell lines MDA-MB 231 and MDA-MB 468. However, and unexpectedly, nilotinib increased by two-fold the invasive properties of the TN breast cancer cell line BT-549 and of Src-transformed fibroblasts. Both display much higher levels of ABL kinase activity compared to MDA-MB 231. Similar effects were obtained by siRNA-mediated down-regulation of ABL expression, confirming ABL central role in this process. ABL anti-tumor effect in BT-549 cells and Src-transformed fibroblasts was not dependent on EGF secretion, as recently reported in neck and squamous carcinoma cells. Rather, we identified the TRIO-RAC1 axis as an important downstream element of ABL activity in these cancer cells. In conclusion, the observation that TN breast cancer cell lines respond differently to ABL inhibitors could have implications for future therapies.

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, 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

Carroll, Daniela J. published the artcileSiglec-8 signals through a non-canonical pathway to cause human eosinophil death in vitro, Category: indole-building-block, the publication is Frontiers in Immunology (2021), 737988, database is CAplus and MEDLINE.

Sialic acid-binding Ig-like lectin (Siglec)-8 is a glycan-binding receptor bearing immunoreceptor tyrosine-based inhibitory and switch motifs (ITIM and ITSM, resp.) that is selectively expressed on eosinophils, mast cells, and, to a lesser extent, basophils. Previous work has shown that engagement of Siglec-8 on IL-5-primed eosinophils causes cell death via CD11b/CD18 integrin-mediated adhesion and NADPH oxidase activity and identified signaling mols. linking adhesion, reactive oxygen species (ROS) production, and cell death. However, the proximal signaling cascade activated directly by Siglec-8 engagement has remained elusive. Most members of the Siglec family possess similar cytoplasmic signaling motifs and recruit the protein tyrosine phosphatases SHP-1/2, consistent with ITIM-mediated signaling, to dampen cellular activation. However, the dependence of Siglec-8 function in eosinophils on these phosphatases has not been studied. Using Siglec-8 antibody engagement and pharmacol. inhibition in conjunction with assays to measure cell-surface upregulation and conformational activation of CD11b integrin, ROS production, and cell death, we sought to identify mols. involved in Siglec-8 signaling and determine the stage of the process in which each mol. plays a role. We demonstrate here that the enzymic activities of Src family kinases (SFKs), Syk, SHIP1, PAK1, MEK1, ERK1/2, PLC, PKC, acid sphingomyelinase/ceramidase, and Btk are all necessary for Siglec-8-induced eosinophil cell death, with no apparent role for SHP-1/2, SHIP2, or c-Raf. While most of these signaling mols. are necessary for Siglec-8- induced upregulation of CD11b integrin at the eosinophil cell surface, Btk is phosphorylated and activated later in the signaling cascade and is instead necessary for CD11b activation. In contrast, SFKs and ERK1/2 are phosphorylated far earlier in the process, consistent with their role in augmenting cell-surface levels of CD11b. In addition, pretreatment of eosinophils with latrunculin B or jasplakinolide revealed that actin filament disassembly is necessary and sufficient for surface CD11b integrin upregulation and that actin polymerization is necessary for downstream ROS production These results show that Siglec-8 signals through an unanticipated set of signaling mols. in IL-5-primed eosinophils to induce cell death and challenges the expectation that ITIM-bearing Siglecs signal through inhibitory pathways involving protein tyrosine phosphatases to achieve their downstream functions.

Frontiers in Immunology 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, 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

Khomula, Eugen V. published the artcilein vitro nociceptor neuroplasticity associated with in vivo opioid-induced hyperalgesia, HPLC of Formula: 330161-87-0, the publication is Journal of Neuroscience (2019), 39(36), 7061-7073, database is CAplus and MEDLINE.

Opioid-induced hyperalgesia (OIH) is a serious adverse event produced by opioid analgesics. Lack of an in-vitro model has hindered study of its underlying mechanisms. Recent evidence has implicated a role of nociceptors in OIH. To investigate the cellular and mol. mechanisms of OIH in nociceptors, in vitro, s.c. administration of an analgesic dose of fentanyl (30μg/kg, s.c.) was performed in vivo in male rats. Two days later, when fentanyl was administered intradermally (1μg, i.d.), in the vicinity of peripheral nociceptor terminals, it produced mech. hyperalgesia (OIH). Addnl., 2 d after systemic fentanyl, rats had also developed hyperalgesic priming (opioid-primed rats), long-lasting nociceptor neuroplasticity manifested as prolongation of prostaglandin E2 (PGE2) hyperalgesia. OIH was reversed, in vivo, by intrathecal administration of cordycepin, a protein translation inhibitor that reverses priming. When fentanyl (0.5 nm) was applied to dorsal root ganglion (DRG) neurons, cultured from opioid-primed rats, it induced a μ-opioid receptor (MOR)-dependent increase in [Ca²⁺]i in 26% of small-diameter neurons and significantly sensitized (decreased action potential rheobase) weakly IB4⁺ and IB4^– neurons. This sensitizing effect of fentanyl was reversed in weakly IB4⁺ DRG neurons cultured from opioid-primed rats after in vivo treatment with cordycepin, to reverse of OIH. Thus, in vivo administration of fentanyl induces nociceptor neuroplasticity, which persists in culture, providing evidence for the role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH.

Journal of 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 C19H21N3O3S, HPLC of Formula: 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

Roller, Devin G. published the artcileSynthetic Lethal Screening with Small-Molecule Inhibitors Provides a Pathway to Rational Combination Therapies for Melanoma, Computed Properties of 330161-87-0, the publication is Molecular Cancer Therapeutics (2012), 11(11), 2505-2515, database is CAplus and MEDLINE.

Recent data show that extracellular signals are transmitted through a network of proteins rather than hierarchical signaling pathways, suggesting that the inhibition of a single component of a canonical pathway is insufficient for the treatment of cancer. The biol. outcome of signaling through a network is inherently more robust and resistant to inhibition of a single network component. In this study, we conducted a functional chem. genetic screen to identify novel interactions between signaling inhibitors that would not be predicted on the basis of our current understanding of signaling networks. We screened over 300 drug combinations in nine melanoma cell lines and have identified pairs of compounds that show synergistic cytotoxicity. The synergistic cytotoxicities identified did not correlate with the known RAS and BRAF mutational status of the melanoma cell lines. Among the most robust results was synergy between sorafenib, a multikinase inhibitor with activity against RAF, and diclofenac, a nonsteroidal anti-inflammatory drug (NSAID). Drug substitution experiments using the NSAIDs celecoxib and ibuprofen or the MAP-ERK kinase inhibitor PD325901 and the RAF inhibitor RAF265 suggest that inhibition of COX and mitogen-activated protein kinase signaling are targets for the synergistic cytotoxicity of sorafenib and diclofenac. Cotreatment with sorafenib and diclofenac interrupts a pos. feedback signaling loop involving extracellular signal-regulated kinase, cellular phospholipase A2, and COX. Genome-wide expression profiling shows synergy-specific downregulation of survival-related genes. This study has uncovered novel functional drug combinations and suggests that the underlying signaling networks that control responses to targeted agents can vary substantially, depending on unexplored components of the cell genotype. Mol Cancer Ther; 11(11); 2505-15. ©2012 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, Computed Properties 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

Morounke, Saibu G. published the artcileGene expression modulation of apoptotic and oestrogen receptor alpha genes by active fractions of selected nigerian plants on cervical cancer cell line (HeLa), Synthetic Route of 192820-78-3, the publication is Tropical Journal of Natural Product Research (2021), 5(4), 772-777, database is CAplus.

The roles of natural product in drug discovery and development cannot be over emphasized. It plays a vital role in human therapy and gives a better understanding on the cellular pathways.This study investigated the modulatory effects of partially purified fractions of Piper guineense Schumach. & Thonn. (Piperaceae), Zanthoxylum zanthoxyloides Lam. (Rutaceae), Amaranthus viridis L. (Amaranthaceae), Costus afer Ker-Gawl. (Zingiberaceae) and Catharanthus roseus (L.) G. Don. (Apocynaceae) on estrogen receptor-α (ESR-α), tumor protein p53 (TP-53), retinoblastoma (RB) and NAD(P) H quinine oxidoreductase (NQO1) genes in cervical cancer cell line (HeLa cells). n-Hexane, ethylacetate, chloroform, and water fractions of 80% ethanol extracts of study plants were screened with brine shrimp lethality and water-soluble tetrazolium-1 (WST-1) cytotoxicity assay. HeLa cells were treated with 1:10 dilutions of IC₅₀ concentrations of test fractions for 24 h, total RNA was extracted, RNA quality was checked, and normalized to a baseline concentration Gene expression were monitored by semi-quant. reverse transcription-polymerase chain reaction (RT-PCR). Results showed that ESR-α was downregulated (p < 0.05) by P. guineense-hexane, C. roseus- chloroform and A. viridis-ethylacetate fractions. TP53 gene was up-regulated (p < 0.05) by P. guineense-hexane and Z. zanthoxyloides-ethylacetate fractions. None of the test fractions caused an up-regulation in the expression of retinoblastoma gene. NQO1 gene was down-regulated (p < 0.05) by C. roseus-chloroform, P. guineense-hexane, A. viridis, C. afer, and Z. zanthoxyloides ethylacetate fractions. Our study provides scientific evidence of the possible anti-proliferative potentials of C. roseus-chloroform, P. guineense-hexane, ethylacetate fractions of A. viridis, C.afer, and Z. zanthoxyloides in cervical cancer.

Tropical Journal of Natural Product 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, Synthetic Route of 192820-78-3.

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

Godwin, Colin D. published the artcileThe Bruton′s tyrosine kinase inhibitor ibrutinib abrogates bispecific antibody-mediated T-cell cytotoxicity, Application of SU6656, the publication is British Journal of Haematology (2020), 189(1), e9-e13, database is CAplus and MEDLINE.

This study examined the abrogation of bispecific antibody (BiAb)-mediated T-cell cytotoxicity by Bruton′s tyrosine kinase inhibitor (BTKi) ibrutinib. Results suggests that ibrutinib-mediated inhibition of BiAb-mediated cancer cell killing is due to an inhibitory effect on T-cell effector function rather than induction of leukemia cell resistance. Together, the studies indicate acute exposure to BTKi impairs T-cell activation and lysis of target cells upon treatment with CD3-directed BiAbs, at least partially due to effects that are independent of BTK inhibition. Further mechanistic studies will be necessary to identify which signaling pathways are involved in this inhibitory effect of BTKi.

British Journal of Haematology 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

Abdelbaset, Mahmoud S. published the artcileDiscovery of novel thienoquinoline-2-carboxamide chalcone derivatives as antiproliferative EGFR tyrosine kinase inhibitors, Name: 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, the publication is Bioorganic & Medicinal Chemistry (2019), 27(6), 1076-1086, database is CAplus and MEDLINE.

Novel thienoquinoline carboxamide-chalcone derivatives were prepared via the cyclization of acylated chalcones and 2-mercaptoquinoline-3-carbaldehyde in DMF with K₂CO₃. Thienoquinolines 9a-f, h exhibited promising antiproliferative effect against all the tested cell lines and gave a significant activity as EGFR inhibitors, with IC₅₀ values ranging from 0.5 and 3.2 μM, and compounds 9e and 9f being the most active of the series. They also showed better activity than Erlotinib against melanoma cancer cell line A375. Moreover, compound 9f influenced pre G1 apoptosis and cell cycle arrest at G2/M phase. The binding mode of the best EGFR inhibitor 9e in the EGFR active site revealed that the thienoquinoline ring occupied the ATP-binding site while the chalcone moiety is located in the allosteric site and is responsible for the enhanced activity of these compounds

Bioorganic & 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 C19H14FN3O3S, Name: 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