1,720,969 research outputs found
Catalyst Controlled Divergent C4/C8 Site-Selective C-H Arylation of Isoquinolones
No full textThe catalyst-controlled C4/C8 site-selective C-H arylation of isoquinolones using aryliodonium salts as the coupling partners was developed. The C4-selective arylation was successfully achieved via an electrophilic palladation pathway. A completely different selectivity pattern was observed using an Ir(III) catalytic system, which resulted in C-C bond formation exclusively at the C8 position. The isoquinolone scaffold can be conveniently equipped with various aryl substituents at either the C4 or C8 position. © 2015 American Chemical Society124241sciescopu
Discovery of Low Micromolar Dual Inhibitors for Wild Type and L1196M Mutant of Anaplastic Lymphoma Kinase through Structure-Based Virtual Screening
No full textAlthough anaplastic lymphoma kinase (ALK) is involved in a variety of malignant human cancers, the emergence of constitutively active mutants with drug resistance has rendered it difficult to identify the new medicines for ALK-dependent cancers. To find the common inhibitors of the wild type ALK and the most abundant drug-resistant mutant (L1196M), we performed molecular docking based virtual screening of a large chemical library in parallel for the two target proteins. As a consequence of augmenting the accuracy of the docking simulation by implementing a sophisticated hydration free energy term in the scoring function, 12 common inhibitors are discovered with the inhibitory activities ranging from submicromolar to low micromolar levels. The results of the binding free energy decomposition indicate that the biochemical potency of ALK inhibitors can be optimized by reducing the dehydration cost for binding to the receptor protein as well as by strengthening the interactions with amino acid residues in the ATP-binding site. The newly identified ALK inhibitors are found to have a little higher inhibitory activity for the L1196M mutant than for the wild type due to the strengthening of the hydrogen bond interactions in the ATP-binding site. Of the 12 common inhibitors, 2-(5-methyl-benzooxazol-2-ylamino)-quinazolin-4-ol (3) is anticipated to serve as a new molecular scaffold to optimize the biochemical potency because it exhibits low micromolar inhibitory activity with respect to both the wild type and L1196M mutant in spite of the low molecular weight (292.3 amu) © 2016 American Chemical Society1341sciescopu
HS-146, a novel phosphoinositide 3-kinase alpha inhibitor, induces the apoptosis and inhibits the metastatic ability of human breast cancer cells
No full textThe phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in human cancer as it regulates critical cellular functions, such as survival, proliferation and metabolism. In the present study, a novel PI3K alpha inhibitor (HS-146) was synthesized and its anticancer effects on MCF-7, MDA-MB-231, SKBR3 and BT-474 human breast cancer cell lines were confirmed. HS-146 was found to be most effective in inhibiting the proliferation of MCF-7 cells and in inducing cell cycle arrest in the G0/G1 phase by downregulating cyclin D1, cyclin E, cyclin-dependent kinase (Cdk)2 and Cdk4, and upregulating p21(Waf1/Cip1) protein levels in this cell line. The induction of apoptosis by HS-146 was confirmed by DAPI staining and western blot analysis. Cell shrinkage and nuclear condensation, which are typical morphological markers of apoptosis, were increased by HS-146 in the MCF-7 cells in a concentration-dependent manner, and HS-146 also increased the protein expression levels of cleaved poly(ADP-ribose) polymerase (PARP) and decreased the protein expression levels of Mcl-1 and caspase-7. In addition, HS-146 effectively decreased the phosphorylation levels of downstream PI3K effectors, such as Akt, mammalian target of rapamycin (mTOR), glycogen synthase kinase 3 beta (GSK3 beta), p70S6K1 and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). Hypoxia-inducible factor (HIF)-1 alpha and vascular endothelial growth factor (VEGF) expression were also suppressed by HS-146 under hypoxic conditions, and HS-146 inhibited the migration and invasion of MCF-7 cells in a concentration-dependent manner. On the whole, the findings of the present study suggest that HS-146, a novel PI3K alpha inhibitor, may be an effective novel therapeutic candidate that suppresses breast cancer proliferation and metastasis by inhibiting the PI3K/Akt/mTOR pathway11sciescopu
Kinase and GPCR polypharmacological approach for the identification of efficient anticancer medicines
No full text© The Royal Society of Chemistry. Discovery of an anticancer medicine using a single target protein has often been unsuccessful due to the complexity of pathogenic mechanisms as well as the presence of redundant signaling pathways. In this work, we attempted to find promising anticancer drug candidates by simultaneously targeting casein kinase 1 delta (CK1δ) and muscarinic acetylcholine receptor M3 (M3R). Through the structure-based virtual screening and de novo design with the modified potential function for protein-ligand binding, a series of benzo[4,5]imidazo[1,2-a][1,3,5]triazine-2-amine (BITA) derivatives were identified as CK1δ inhibitors and also as M3R antagonists. The biochemical potencies of these bifunctional molecules reached the nanomolar and low-micromolar levels with respect to CK1δ and M3R, respectively. A common interaction feature in the calculated CK1δ-inhibitor and M3R-antagonist complexes is that the BITA moiety is well-stabilized in the orthosteric site of M3R and the hinge region of CK1δ through the establishment of the three hydrogen bonds and the hydrophobic contacts in the vicinity. The computational and experimental results found in this work exemplify the efficiency of kinase and GPCR polypharmacology in developing anticancer medicines. This journal i11sciescopu
Discovery of fluorescent 3-heteroarylcoumarin derivatives as novel inhibitors of anaplastic lymphoma kinase
No full textAltered expression or hyperactivation of anaplastic lymphoma kinase (ALK), as a consequence of translocations or point mutations, is one of the main oncogenic drivers in non-small cell lung cancer. Using structure-based design and in vitro enzyme assays, we identified 3-heteroarylcoumarin as a new template for the development of novel fluorescent ALK inhibitors. Molecular simulation provided structural insights for the design of 3-heteroarylcoumarin derivatives, which were easily prepared through efficient synthetic approaches including direct C-H cross coupling. Importantly, these coumarin-based ALK inhibitors can be tracked using microscopy techniques: we illustrated the use of the most potent compound in this series, 5a, (ALK/IC50 = 0.51 M, (emi) = 500 nm, phi(F) = 0.29) to monitor its subcellular distribution pattern by confocal fluorescence microscopy © The Royal Society of Chemistry 201
HS-1371, a novel kinase inhibitor of RIP3-mediated necroptosis
Full text linkNecroptosis is a type of programmed cell death that usually occurs under apoptosis-deficient conditions. Receptor-interacting protein kinase-3 (RIP3, or RIPK3) is a central player in necroptosis, and its kinase activity is essential for downstream necroptotic signaling events. Since RIP3 kinase activity has been associated with various diseases, the development of specific RIP3 inhibitors is an attractive strategy for therapeutic application. In this study, we identified a potent RIP3 inhibitor, HS-1371, by the extensive screening of chemical libraries focused on kinases. HS-1371 directly binds to RIP3 in an ATP-competitive and time-independent manner, providing a mechanism of action. Moreover, the compound inhibited TNF-induced necroptosis but did not inhibit TNF-induced apoptosis, indicating that this novel inhibitor has a specific inhibitory effect on RIP3-mediated necroptosis via the suppression of RIP3 kinase activity. Our results suggest that HS-1371 could serve as a potential preventive or therapeutic agent for diseases involving RIP3 hyperactivation © The Author(s) 201
Fascaplysin Exerts Anti-Cancer Effects through the Downregulation of Survivin and HIF-1α and Inhibition of VEGFR2 and TRKA
Full text linkFascaplysin has been reported to exert anti-cancer effects by inhibiting cyclin-dependent kinase 4 (CDK4); however, the precise mode of action by which fascaplysin suppresses tumor growth is not clear. Here, we found that fascaplysin has stronger anti-cancer effects than other CDK4 inhibitors, including PD0332991 and LY2835219, on lung cancer cells that are wild-type or null for retinoblastoma (RB), indicating that unknown target molecules might be involved in the inhibition of tumor growth by fascaplysin. Fascaplysin treatment significantly decreased tumor angiogenesis and increased cleaved-caspase-3 in xenografted tumor tissues. In addition, survivin and HIF-1α were downregulated in vitro and in vivo by suppressing 4EBP1-p70S6K1 axis-mediated de novo protein synthesis. Kinase screening assays and drug-protein docking simulation studies demonstrated that fascaplysin strongly inhibited vascular endothelial growth factor receptor 2 (VEGFR2) and tropomyosin-related kinase A (TRKA) via DFG-out non-competitive inhibition. Overall, these results suggest that fascaplysin inhibits TRKA and VEGFR2 and downregulates survivin and HIF-1α, resulting in suppression of tumor growth. Fascaplysin, therefore, represents a potential therapeutic approach for the treatment of multiple types of solid cancer. © 2017 by the authors111sci
HS-173 as a novel inducer of RIP3-dependent necroptosis in lung cancer
No full textNecroptosis is a form of regulated necrotic cell death mediated by receptor-interacting kinase 3 (RIP3). Recently, necroptosis has gained attention as a novel alternative therapy to target cancer cells. In this study, we screened several chemotherapeutics used in preclinical and clinical studies, and identified a drug HS-173 that induces RIP3-mediated necroptosis. HS-173 decreased the cell survival in a dose-dependent manner in RIP3-expressing lung cancer cells, compared to the cells lacking RIP3. Also, the cell death induced by HS-173 was rescued by specific necroptosis inhibitors such as necrostatin-1 and dabrafenib. Additionally, HS-173 increased the phosphorylation of RIP3 and MLKL, which was decreased by necroptosis inhibitors, indicating that HS-173 activates RIP3/MLKL signaling in lung cancer cells. HS-173 increased the necroptotic events, as observed by the increased levels of HMGB1 and necroptotic morphological features. Furthermore, HS-173 inhibited the tumor growth by stimulation of necroptosis in mouse xenograft models. Our findings offer new insights into the role of HS-173 in inducing necroptosis by enhancing RIP3 expression and activating the RIP3/MLKL signaling pathway in lung cancer cells. © 2018 Elsevier B.V11sciescopu
Identification of 4-Phenoxyquinoline Based Inhibitors for L1196M Mutant of Anaplastic Lymphoma Kinase by Structure-Based Design
No full textDysregulation of anaplastic lymphoma kinase (ALK) has been detected in nonsmall cell lung cancer (NSCLC) in the form of EML4-ALK fusion. Secondary mutations opposing activity of the first generation ALK inhibitor crizotinib came into existence, requiring mutation-targeting drug discovery for the powerful second-line treatment. In this study, we report 4-phenoxyquinoline-based inhibitors that overcome crizotinib resistance to ALK L1196M, discovered by the fragment-growing strategy. The protonation of 4-aminoquinoline core could interrupt the ability the N atom of quinoline to act as a hydrogen bond acceptor; therefore, the pK(a) and calculated ionization pH values of relevant pyridine-based core moieties were carefully analyzed. The replacement of amine linkage with ether resulted in single-digit nanomolar range inhibitors. The inhibitors exhibited significant antiproliferative effects on H2228 CR crizotinib-resistant cells by decreasing PI3K/AKT and MAPK signaling. This work constitutes the first of ionization pH on activity in this system © 2017 American Chemical Society11sciescopu
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