Search results for: DiscoveryPak™ Hedgehog (Hh) Signaling Pathway Inhibitors Set
#28787156 2017/08/08 Save this To Up
Dual MET and SMO Negative Modulators Overcome Resistance to EGFR Inhibitors in Human Nonsmall Cell Lung Cancer.Tyrosine kinase inhibitors (TKIs) of the EGF receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, resistance to these agents frequently occurs, and it is often related to the activation of the Hedgehog (Hh) and MET signaling cascades driving the epithelial-to-mesenchymal transition (EMT). Because the concomitant inhibition of both Hh and MET pathways restores the sensitivity to anti-EGFR drugs, here we aimed at discovering the first compounds that block simultaneously MET and SMO. By using an "in silico drug repurposing" approach and by validating our predictions both in vitro and in vivo, we identified a set of compounds with the desired dual inhibitory activity and enhanced antiproliferative activity on EGFR TKI-resistant NSCLC. The identification of the known MET TKIs, glesatinib and foretinib, as negative modulators of the Hh pathway, widens their application in the context of NSCLC.
2914 related Products with: Dual MET and SMO Negative Modulators Overcome Resistance to EGFR Inhibitors in Human Nonsmall Cell Lung Cancer.Cell Meter™ Fluorimetri Cell Meter™ Fluorimetri Nycodenz, non ionic, non Lung non small cell cance Lung cancer tissue array Oral squamous cell cancer Non-small cell lung cance Top 4 types of cancer (co Top 4 types of cancer (co CELLKINES Natural Human I Macrophage Colony Stimula Macrophage Colony Stimula
#28618224 2017/06/15 Save this To Up
Design, Synthesis, and Structure-Activity Relationship of Tetrahydropyrido[4,3-d]pyrimidine Derivatives as Potent Smoothened Antagonists with in Vivo Activity.Medulloblastoma is one of the most prevalent brain tumors in children. Aberrant hedgehog (Hh) pathway signaling is thought to be involved in the initiation and development of medulloblastoma. Vismodegib, the first FDA-approved cancer therapy based on inhibition of aberrant hedgehog signaling, targets smoothened (Smo), a G-protein coupled receptor (GPCR) central to the Hh pathway. Although vismodegib exhibits promising therapeutic efficacy in tumor treatment, concerns have been raised from its nonlinear pharmacokinetic (PK) profiles at high doses partly due to low aqueous solubility. Many patients experience adverse events such as muscle spasms and weight loss. In addition, drug resistance often arises among tumor cells during treatment with vismodegib. There is clearly an urgent need to explore novel Smo antagonists with improved potency and efficacy. Through a scaffold hopping strategy, we have identified a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives, which exhibited effective inhibition of Hh signaling. Among them, compound 24 is three times more potent than vismodegib in the NIH3T3-GRE-Luc reporter gene assay. Compound 24 has a lower melting point and much greater solubility compared with vismodegib, resulting in linear PK profiles when dosed orally at 10, 30, and 100 mg/kg in rats. Furthermore, compound 24 showed excellent PK profiles with a 72% oral bioavailability in beagle dogs. Compound 24 demonstrated overall favorable in vitro safety profiles with respect to CYP isoform and hERG inhibition. Finally, compound 24 led to significant regression of subcutaneous tumor generated by primary Ptch1-deficient medulloblastoma cells in SCID mouse. In conclusion, tetrahydropyrido[4,3-d]pyrimidine derivatives represent a novel set of Smo inhibitors that could potentially be utilized to treat medulloblastoma and other Hh pathway related malignancies.
1060 related Products with: Design, Synthesis, and Structure-Activity Relationship of Tetrahydropyrido[4,3-d]pyrimidine Derivatives as Potent Smoothened Antagonists with in Vivo Activity.Cell Meter™ Fluorimetri Cell Meter™ Fluorimetri Alkaline Phospatase (ALP) ELISA kit CLGI,Collagenas EnzyChrom™ Kinase Assay MarkerGeneTM in vivo lacZ MarkerGeneTM Fluorescent MarkerGeneTM Live Dead As MarkerGeneTM Long Wavelen MarkerGeneTMFluorescent A EpiQuik Histone Methyltra EpiQuik Histone Methyltra
#28487292 2017/05/10 Save this To Up
GLI3 repressor determines Hedgehog pathway activation and is required for response to SMO antagonist glasdegib in AML.The Hedgehog (Hh) signaling pathway is activated in many cancers and is a promising target for therapeutic development. Deletions in the receptor Patched (PTCH) or activating mutations in Smoothened (SMO) have been reported in basal cell carcinoma and medulloblastoma, but are largely absent in most tumor types. Therefore, the mechanism of pathway activation in most cancers, including hematological malignancies, remains unknown. In normal tissues, Hh pathway activation via PTCH/SMO causes an increase in the downstream transcriptional activator GLI1 and a decrease in the GLI3 transcriptional repressor (GLI3R). In this article, we confirm that the Hh pathway is active in acute myeloid leukemia (AML), however, this activity is largely independent of SMO. Epigenetic and gene expression analysis of The Cancer Genome Atlas AML data set reveals that GLI3 expression is silenced in most AML patient samples, and the GLI3 locus is abnormally methylated. We show that GLI3R is required for the therapeutic effect of SMO antagonists in AML samples and restoration of GLI3R suppresses the growth of AML. We additionally demonstrate that GLI3R represses AML growth by downregulating AKT expression. In summary, this study provides the first evidence that GLI3R plays an essential role in SMO-independent Hh signaling in AML, and suggests that GLI3R could serve as a potential biomarker for patient selection in SMO antagonist clinical trials. Furthermore, these data support rational combinations of hypomethylating agents with SMO antagonists in clinical trials.
1374 related Products with: GLI3 repressor determines Hedgehog pathway activation and is required for response to SMO antagonist glasdegib in AML.DiscoveryPak™ Hedgehog Interleukin-34 IL34 (N-t Interleukin-34 IL34 anti MOUSE ANTI BOVINE ROTAVIR Anti AGO2 Human, Monoclon Anti AGO2 Mouse, Monoclon Anti AGO2 Human, Monoclon Anti AGO2 Mouse, Monoclon HIV1 integrase antibody, Shiga Toxin 1 antibody, M Shiga Toxin 2 antibody, M Cholera toxin antibody, M
#27899820 2016/11/30 Save this To Up
Inhibition of Hedgehog-dependent tumors and cancer stem cells by a newly identified naturally occurring chemotype.Hedgehog (Hh) inhibitors have emerged as valid tools in the treatment of a wide range of cancers. Indeed, aberrant activation of the Hh pathway occurring either by ligand-dependent or -independent mechanisms is a key driver in tumorigenesis. The smoothened (Smo) receptor is one of the main upstream transducers of the Hh signaling and is a validated target for the development of anticancer compounds, as underlined by the FDA-approved Smo antagonist Vismodegib (GDC-0449/Erivedge) for the treatment of basal cell carcinoma. However, Smo mutations that confer constitutive activity and drug resistance have emerged during treatment with Vismodegib. For this reason, the development of new effective Hh inhibitors represents a major challenge for cancer therapy. Natural products have always represented a unique source of lead structures in drug discovery, and in recent years have been used to modulate the Hh pathway at multiple levels. Here, starting from an in house library of natural compounds and their derivatives, we discovered novel chemotypes of Hh inhibitors by mean of virtual screening against the crystallographic structure of Smo. Hh functional based assay identified the chalcone derivative 12 as the most effective Hh inhibitor within the test set. The chalcone 12 binds the Smo receptor and promotes the displacement of Bodipy-Cyclopamine in both Smo WT and drug-resistant Smo mutant. Our molecule stands as a promising Smo antagonist able to specifically impair the growth of Hh-dependent tumor cells in vitro and in vivo and medulloblastoma stem-like cells and potentially overcome the associated drug resistance.
1169 related Products with: Inhibition of Hedgehog-dependent tumors and cancer stem cells by a newly identified naturally occurring chemotype.Combined multiple normal Breast cancer tissue arra Dog Receptor-binding canc CA125, Ovarian Cancer An CA125, Ovarian Cancer An CA125, Ovarian Cancer An Fontana-Masson Stain Kit Fontana-Masson Stain Kit Anti C Reactive Protein A anti HSV (II) gB IgG1 (mo anti HCMV IE pp65 IgG1 (m anti HCMV gB IgG1 (monocl
#27157927 2016/05/09 Save this To Up
Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia.Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34(+) CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34(+) CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34(+) CP-CML cell engraftment in NSG mice and, upon administration to EGFP(+) /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells.
1381 related Products with: Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia.DiscoveryPak™ Hedgehog Hh Signaling Pathway Anta Anti 3 DG imidazolone Mon AKT PKB Signaling Phospho AMPK Signaling Phospho-Sp ErbB Her Signaling Phosph ERK Signaling Phospho-Spe GPCR Signaling to MAPK ER IGF-1R Signaling Phospho- NF-kB II Phospho-Specific p53 Signaling Phospho-Spe T-Cell Receptor Signaling
#25473003 2015/02/03 Save this To Up
A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma.Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway-activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway-activated medulloblastoma.
1766 related Products with: A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma.EMAP-II Inhibitor Z-ASTD- EMAP-II Inhibitor Z-ASTD- EMAP II Inhibitor Z ASTD EMAP II Inhibitor Z ASTD MMP-13 inhibitor assay ki MMP13 inhibitor assay kit ASP-3026 Mechanisms: ALK EnzyChrom™ Kinase Assay Rat anti human Indian Hed Caspase 1 Inhibitor Drug Caspase 2 Inhibitor Drug Caspase 3 Inhibitor Drug
#22204396 2012/04/23 Save this To Up
Pharmacological modulation of the Hedgehog pathway differentially affects dorsal/ventral patterning in mouse and human embryonic stem cell models of telencephalic development.A complex set of extrinsic and intrinsic signals acts in specific temporal and spatial orders to enable neural differentiation during development. These processes have been extensively studied in animal models, but human neural development remains much less understood. This lack of detailed information about human early neurogenesis is a hindrance for the differentiation of pluripotent stem cell lines into specific neuronal phenotypes. Therefore, it is important to strengthen the interspecies comparative approaches. We describe a novel model system in which in vitro differentiation of human and mouse embryonic stem (ES) cells are temporally aligned to each other and compared with mouse telencephalic neurogenesis in vivo. In this comparative model system, we tested the in vitro role of Hedgehog (Hh) signaling for ES cell-derived telencephalic differentiation. In vivo, Hh signaling mediates dorsal/ventral patterning during early stages of telencephalic development. We monitored the effect of pharmacological modulators of the Hh signaling pathway, purmorphamine-an agonist and cyclopamine-an antagonist of the Smoothened receptor (Smo), on the expression of region-specific transcription factors and signaling molecules relevant for telencephalic development in vivo. Purmorphamine strongly upregulated the expression of telencephalic ventral markers Nkx2.1, Nkx6.2, Lhx6, and Lhx8 in mouse and human cells, thus reflecting the in vivo process of the medial ganglionic eminence patterning and specification. Cyclopamine upregulated the expression of telencephalic dorsal markers, but at lower levels in human compared with mouse cells. Modulation of Smo in vitro differentially affected, in mouse and human cells, the expression of molecules of the Hh pathway, especially the Gli1 and Gli3 effectors, Sonic Hh ligand and Ptch receptors. These results provide evidence for the different default differentiation of mouse and human ES cells and prove the utility of the comparative system for optimizing the directed differentiation of human pluripotent stem cells.
1951 related Products with: Pharmacological modulation of the Hedgehog pathway differentially affects dorsal/ventral patterning in mouse and human embryonic stem cell models of telencephalic development.Macrophage Colony Stimula Macrophage Colony Stimula Rabbit Anti-Cell death in Rabbit Anti-Cell death in 129 Mouse Embryonic Stem CELLKINES Natural Human I Human Stem Cell Factor SC Goat Anti-Human, Mouse HI Goat Anti-Human FTO (Mous Goat Anti-Human, Mouse EB Goat Anti-Human, Mouse, R Goat Anti-Human, Mouse, R
#20434536 2010/06/11 Save this To Up
Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening.In animal models, chemical disruption of the Hedgehog (Hh) signaling pathway during embryonic development causes severe birth defects including holoprosencephaly and cleft lip and palate. The exact etiological basis of correlate human birth defects remains uncertain but is likely multifactorial, involving the interaction of genetic and environmental or chemical influences. The Hh transduction mechanism relies upon endogenous small molecule regulation, conferring remarkable pathway sensitivity to inhibition by a structurally diverse set of exogenous small molecules. Here, we employed small molecule screening to identify human exposure-relevant Hh signaling inhibitors. From a library of 4240 compounds, including pharmaceuticals, natural products, and pesticides, three putative Hh pathway inhibitors were identified: tolnaftate, an antifungal agent; ipriflavone, a dietary supplement; and 17-beta-estradiol, a human hormone and pharmaceutical agent. Each compound inhibited Hh signaling in both mouse and human cells. Dose-response assays determined the three compounds to be 8- to 30-fold less potent than the index Hh pathway inhibitor cyclopamine. Despite current limitations in chemical library availability, which narrowed the scope of this study to only a small fraction of all human exposure-relevant small molecules, three structurally diverse environmental Hh signaling inhibitors were identified, highlighting an inherent pathway vulnerability to teratogenic influences.
1315 related Products with: Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening.DiscoveryPak™ Hedgehog Human Sonic Hedgehog SHH Sonic Hedgehog (SHH), hum Sonic Hedgehog (SHH), hum Sonic Hedgehog (SHH), hum IGF-1R Signaling (Human) Human T Cell Receptor Sig Human Small Intestine Mic Human intercellular adhes Human vascular cell adhes Human soluble vascular ce Mouse Anti-Human Fibronec
#19666565 2009/08/26 Save this To Up
Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade.Inappropriate activation of the Hedgehog (Hh) signaling pathway has been implicated in a diverse spectrum of cancers, and its pharmacological blockade has emerged as an anti-tumor strategy. While nearly all known Hh pathway antagonists target the transmembrane protein Smoothened (Smo), small molecules that suppress downstream effectors could more comprehensively remediate Hh pathway-dependent tumors. We report here four Hh pathway antagonists that are epistatic to the nucleocytoplasmic regulator Suppressor of Fused [Su(fu)], including two that can inhibit Hh target gene expression induced by overexpression of the Gli transcription factors. Each inhibitor has a unique mechanism of action, and their phenotypes reveal that Gli processing, Gli activation, and primary cilia formation are pharmacologically targetable. We further establish the ability of certain compounds to block the proliferation of cerebellar granule neuron precursors expressing an oncogenic form of Smo, and we demonstrate that Hh pathway inhibitors can have tissue-specific activities. These antagonists therefore constitute a valuable set of chemical tools for interrogating downstream Hh signaling mechanisms and for developing chemotherapies against Hh pathway-related cancers.
1395 related Products with: Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade.DiscoveryPak™ Hedgehog Multiple lung carcinoma ( Gli Reporter – NIH3T3 C Multiple organ stromal tu PathwayReady™ PI3 K Akt PathwayReady™ MAP Kinas PathwayReady™ EGFR Sign PathwayReady™ JAK STAT Multiple non small cell l Cellufine Formyl , 50 ml Cellufine Formyl Media Cellufine Formyl , 500 ml
#18411234 2008/06/09 Save this To Up
Dose- and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the hedgehog signaling antagonist cyclopamine in the mouse.The Hedgehog (Hh) signaling pathway is an essential regulator of embryonic development and appears to play important roles in postnatal repair and cancer progression and metastasis. The teratogenic Veratrum alkaloid cyclopamine is a potent Hh antagonist and is used experimentally both in vitro and in vivo to investigate the role of Hh signaling in diverse biological processes. Here, we set out to establish an administration regimen for cyclopamine-induced teratogenicity in the mouse. The dysmorphogenic concentration of cyclopamine was determined in vitro via mouse whole-embryo culture assays to be 2.0 microM. We administered cyclopamine to female C57BL/6J mice at varied doses by oral gavage, ip injection, or osmotic pump infusion and assessed toxicity and pharmacokinetic (PK) models. Bolus administration was limited by toxicity and rapid clearance. In vivo cyclopamine infusion at 160 mg/kg/day yielded a dam serum steady-state concentration of approximately 2 microM with a corresponding amniotic fluid concentration of approximately 1.5 microM. Gross facial defects were induced in 30% of cyclopamine-exposed litters, with affected embryos exhibiting cleft lip and palate. This is the first report describing the PKs and teratogenic potential of cyclopamine in the mouse and demonstrates that transient Hh signaling inhibition induces facial clefting anomalies in the mouse that mimic common human birth defects.
1248 related Products with: Dose- and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the hedgehog signaling antagonist cyclopamine in the mouse.Cyclopamine Mechanisms: H AZD-3514 Mechanisms: Andr Thermal Shaker with cooli CAR,Car,Constitutive andr FDA Standard Frozen Tissu FDA Standard Frozen Tissu FDA Standard Frozen Tissu FDA Standard Frozen Tissu FDA Standard Frozen Tissu FDA Standard Frozen Tissu Normal mouse multiple org Mouse Protein Z-Dependent
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