Hedgehog-Gli signaling pathway inhibitors as anticancer agents.

PubWeight™: 1.14‹?› | Rank: Top 10%

🔗 View Article (PMC 2743241)

Published in J Med Chem on July 09, 2009

Authors

Neeraj Mahindroo1, Chandanamali Punchihewa, Naoaki Fujii

Author Affiliations

1: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. Neeraj.Mahindroo@stjude.org

Associated clinical trials:

A Phase 1 Study of BMS-833923 (XL139) in Subjects With Advanced or Metastatic Cancer | NCT00670189

A Phase 1 Study of IPI-926 in Patients With Advanced and/or Metastatic Solid Tumor Malignancies | NCT00761696

Articles citing this

Targeting Hedgehog--a cancer stem cell pathway. Clin Cancer Res (2010) 2.50

Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist. ACS Med Chem Lett (2010) 1.68

Forkhead box M1 transcription factor: a novel target for cancer therapy. Cancer Treat Rev (2009) 1.63

Structural basis for Smoothened receptor modulation and chemoresistance to anticancer drugs. Nat Commun (2014) 1.05

Femtosecond crystallography of membrane proteins in the lipidic cubic phase. Philos Trans R Soc Lond B Biol Sci (2014) 1.01

A hedgehog survival pathway in 'undead' lipotoxic hepatocytes. J Hepatol (2012) 0.95

Amide conjugates of ketoprofen and indole as inhibitors of Gli1-mediated transcription in the Hedgehog pathway. Bioorg Med Chem (2010) 0.89

Aberrant GLI1 Activation in DNA Damage Response, Carcinogenesis and Chemoresistance. Cancers (Basel) (2015) 0.86

BMI1 polycomb group protein acts as a master switch for growth and death of tumor cells: regulates TCF4-transcriptional factor-induced BCL2 signaling. PLoS One (2013) 0.86

Enhancement of cyclopamine via conjugation with nonmetabolic sugars. Org Lett (2012) 0.82

Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies. ACS Med Chem Lett (2012) 0.81

Structure-activity relationships and cancer-cell selective toxicity of novel inhibitors of glioma-associated oncogene homologue 1 (Gli1) mediated transcription. J Med Chem (2009) 0.81

Identification of a novel Smoothened antagonist that potently suppresses Hedgehog signaling. Bioorg Med Chem (2012) 0.79

Prevention of pancreatic cancer in a hamster model by cAMP decrease. Oncotarget (2016) 0.75

Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors. Beilstein J Org Chem (2012) 0.75

Development of thieno- and benzopyrimidinone inhibitors of the Hedgehog signaling pathway reveals PDE4-dependent and PDE4-independent mechanisms of action. Bioorg Med Chem Lett (2016) 0.75

Gender-Dependent Pharmacokinetics of Veratramine in Rats: In Vivo and In Vitro Evidence. AAPS J (2016) 0.75

Pharmacological targeting of GLI1 inhibits proliferation, tumor emboli formation and in vivo tumor growth of inflammatory breast cancer cells. Cancer Lett (2017) 0.75

Molecular basis of basal cell carcinoma. An Bras Dermatol (2017) 0.75

Articles cited by this

(truncated to the top 100)

Mutations affecting segment number and polarity in Drosophila. Nature (1980) 18.72

Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature (2002) 15.36

Hedgehog signaling in animal development: paradigms and principles. Genes Dev (2001) 14.75

Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature (2003) 10.33

Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature (2000) 10.04

Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev (2002) 8.56

A paracrine requirement for hedgehog signalling in cancer. Nature (2008) 8.16

Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science (1996) 8.06

Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature (1998) 7.43

Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell (1993) 7.41

Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature (2004) 6.82

Small molecule modulation of Smoothened activity. Proc Natl Acad Sci U S A (2002) 6.55

Medulloblastoma growth inhibition by hedgehog pathway blockade. Science (2002) 6.53

Tissue repair and stem cell renewal in carcinogenesis. Nature (2004) 6.28

Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature (2003) 6.07

Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice. Cancer Cell (2004) 5.95

The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature (1996) 5.69

Hedgehog: functions and mechanisms. Genes Dev (2008) 5.69

Cholesterol modification of hedgehog signaling proteins in animal development. Science (1996) 5.66

Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov (2006) 5.30

Teratogen-mediated inhibition of target tissue response to Shh signaling. Science (1998) 5.28

The Hedgehog response network: sensors, switches, and routers. Science (2004) 5.20

HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol (2006) 5.17

Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res (2007) 5.12

Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer (2003) 4.86

The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet (1996) 4.36

Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer (2008) 4.34

GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev (2009) 4.21

Identification of an amplified, highly expressed gene in a human glioma. Science (1987) 4.21

Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci U S A (2007) 4.15

A mouse model of greig cephalopolysyndactyly syndrome: the extra-toesJ mutation contains an intragenic deletion of the Gli3 gene. Nat Genet (1993) 3.99

Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci (2003) 3.98

Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer (2002) 3.91

Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development (2000) 3.91

The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development (1998) 3.89

Mutations in SUFU predispose to medulloblastoma. Nat Genet (2002) 3.78

Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron (2003) 3.76

Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat Med (1998) 3.75

Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc Natl Acad Sci U S A (2004) 3.68

Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development (1997) 3.66

Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell (2006) 3.62

Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nat Genet (1996) 3.50

Purmorphamine activates the Hedgehog pathway by targeting Smoothened. Nat Chem Biol (2005) 3.49

Oncoprotein networks. Cell (1997) 3.42

Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J Biol Chem (1999) 3.25

Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci U S A (2007) 3.20

The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development (2001) 3.14

The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol (2007) 3.14

Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem (1998) 2.95

Autoproteolysis in hedgehog protein biogenesis. Science (1994) 2.87

Gli proteins encode context-dependent positive and negative functions: implications for development and disease. Development (1999) 2.77

Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci U S A (2000) 2.73

Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell (1994) 2.58

Mosaic removal of hedgehog signaling in the adult SVZ reveals that the residual wild-type stem cells have a limited capacity for self-renewal. J Neurosci (2007) 2.56

Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J Biol Chem (2001) 2.56

Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology (2004) 2.47

Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. Cancer Cell (2008) 2.42

Oncogenic KRAS activates hedgehog signaling pathway in pancreatic cancer cells. J Biol Chem (2007) 2.34

Activation of the hedgehog pathway in advanced prostate cancer. Mol Cancer (2004) 2.32

Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci U S A (2003) 2.25

A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat Chem Biol (2009) 2.21

An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol Cancer Ther (2008) 2.21

Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci U S A (2007) 2.17

Divergence of hedgehog signal transduction mechanism between Drosophila and mammals. Dev Cell (2006) 2.12

Gli1 is important for medulloblastoma formation in Ptc1+/- mice. Oncogene (2005) 1.92

Shh pathway activity is down-regulated in cultured medulloblastoma cells: implications for preclinical studies. Cancer Res (2006) 1.90

Hedgehog acts as a somatic stem cell factor in the Drosophila ovary. Nature (2001) 1.89

Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J Pathol (2006) 1.83

Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene (2007) 1.78

In vivo inhibition of endogenous brain tumors through systemic interference of Hedgehog signaling in mice. Mech Dev (2005) 1.76

Genetic analysis of zebrafish gli1 and gli2 reveals divergent requirements for gli genes in vertebrate development. Development (2003) 1.76

Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation. J Cell Sci (2001) 1.74

Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli-1. Neuron (1997) 1.65

GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. Proc Natl Acad Sci U S A (1999) 1.63

REN(KCTD11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma. Proc Natl Acad Sci U S A (2004) 1.63

The hedgehog signaling molecule Gli2 induces parathyroid hormone-related peptide expression and osteolysis in metastatic human breast cancer cells. Cancer Res (2006) 1.62

Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. J Biol Chem (2002) 1.60

Gli activity correlates with tumor grade in platelet-derived growth factor-induced gliomas. Cancer Res (2008) 1.60

Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Cell (2008) 1.58

Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. Mol Biol Cell (2007) 1.57

A CONGENITAL CYCLOPIAN-TYPE MALFORMATION IN LAMBS INDUCED BY MATERNAL INGESTION OF A RANGE PLANT, VERATRUM CALIFORNICUM. Am J Vet Res (1963) 1.53

Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase. J Biol Chem (2006) 1.51

Protein kinase C-delta and mitogen-activated protein/extracellular signal-regulated kinase-1 control GLI activation in hedgehog signaling. Cancer Res (2006) 1.49

Hedgehog signalling in colorectal tumour cells: induction of apoptosis with cyclopamine treatment. Int J Cancer (2004) 1.41

Role of hedgehog signaling in ovarian cancer. Clin Cancer Res (2008) 1.36

Targeting medulloblastoma: small-molecule inhibitors of the Sonic Hedgehog pathway as potential cancer therapeutics. Cancer Res (2005) 1.35

Activation of the hedgehog pathway in a subset of lung cancers. Cancer Lett (2006) 1.34

The hedgehog regulated oncogenes Gli1 and Gli2 block myoblast differentiation by inhibiting MyoD-mediated transcriptional activation. Oncogene (2006) 1.32

Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice. J Clin Invest (2008) 1.32

Gli-1 expression is associated with lymph node metastasis and tumor progression in esophageal squamous cell carcinoma. Oncology (2006) 1.28

Teratogenic compounds of Veratrum californicum (Durand). V. Comparison of cyclopian effects of steroidal alkaloids from the plant and structurally related compounds from other sources. Teratology (1968) 1.27

Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation. Cancer Res (1996) 1.25

Hedgehog stimulates only osteoblastic differentiation of undifferentiated KS483 cells. Bone (2003) 1.23

Hedgehog antagonist REN(KCTD11) regulates proliferation and apoptosis of developing granule cell progenitors. J Neurosci (2005) 1.19

Sonic hedgehog-Gli1 pathway in colorectal adenocarcinomas. World J Gastroenterol (2007) 1.18

Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription. Chembiochem (2008) 1.14

Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists. J Med Chem (2008) 1.07

Medulloblastoma: molecular genetics and animal models. Neoplasia (2004) 1.07

Targeted inhibition of hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer. Bioorg Med Chem (2008) 1.06

Hedgehog signaling pathway: development of antagonists for cancer therapy. Curr Oncol Rep (2008) 1.05

Articles by these authors

Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet (2013) 3.51

Structure of the Hybrid-2 type intramolecular human telomeric G-quadruplex in K+ solution: insights into structure polymorphism of the human telomeric sequence. Nucleic Acids Res (2007) 2.23

Structure of the intramolecular human telomeric G-quadruplex in potassium solution: a novel adenine triple formation. Nucleic Acids Res (2007) 1.72

An anti-Wnt-2 monoclonal antibody induces apoptosis in malignant melanoma cells and inhibits tumor growth. Cancer Res (2004) 1.64

Functional regulation of cystic fibrosis transmembrane conductance regulator-containing macromolecular complexes: a small-molecule inhibitor approach. Biochem J (2011) 1.55

Mechanism of ubiquitin ligation and lysine prioritization by a HECT E3. Elife (2013) 1.27

Role of electrostatic interactions in PDZ domain ligand recognition. Biochemistry (2003) 1.13

Identification of small molecule proliferating cell nuclear antigen (PCNA) inhibitor that disrupts interactions with PIP-box proteins and inhibits DNA replication. J Biol Chem (2012) 1.03

Recent advances and new perspectives in targeting CFTR for therapy of cystic fibrosis and enterotoxin-induced secretory diarrheas. Future Med Chem (2012) 1.00

Rational design of the first small-molecule antagonists of NHERF1/EBP50 PDZ domains. Bioorg Med Chem Lett (2007) 1.00

Sequence requirement and subtype specificity in the high-affinity interaction between human frizzled and dishevelled proteins. Protein Sci (2009) 0.92

Amide conjugates of ketoprofen and indole as inhibitors of Gli1-mediated transcription in the Hedgehog pathway. Bioorg Med Chem (2010) 0.89

Partial acetylation of lysine residues improves intraprotein cross-linking. Anal Chem (2008) 0.89

A small molecule inhibitor of monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA) inhibits repair of interstrand DNA cross-link, enhances DNA double strand break, and sensitizes cancer cells to cisplatin. J Biol Chem (2014) 0.88

Indole-2-amide based biochemical antagonist of Dishevelled PDZ domain interaction down-regulates Dishevelled-driven Tcf transcriptional activity. Bioorg Med Chem Lett (2007) 0.87

Small molecule inhibitors of PCNA/PIP-box interaction suppress translesion DNA synthesis. Bioorg Med Chem (2013) 0.86

Evaluation of a chemical library of small-molecule Dishevelled antagonists that suppress tumor growth by down-regulating T-cell factor-mediated transcription. Mol Cancer Ther (2008) 0.81

Structure-activity relationships and cancer-cell selective toxicity of novel inhibitors of glioma-associated oncogene homologue 1 (Gli1) mediated transcription. J Med Chem (2009) 0.81

Discovery of diphenyloxazole and Ndelta-Z-ornithine derivatives as highly potent and selective human prostaglandin EP(4) receptor antagonists. J Med Chem (2005) 0.77

Investigation of the PDZ domain ligand binding site using chemically modified peptides. Bioorg Med Chem Lett (2002) 0.77

Posterior fossa and spinal gangliogliomas form two distinct clinicopathologic and molecular subgroups. Acta Neuropathol Commun (2014) 0.77

A structure-activity relationship study of small-molecule inhibitors of GLI1-mediated transcription. Biopolymers (2011) 0.76

The hydrophobic amino acid cluster at the cytoplasmic end of transmembrane helix III modulates the coupling of the β(1)-adrenergic receptor to G(s). J Recept Signal Transduct Res (2013) 0.75

Potential Strategies to Target Protein-Protein Interactions in the DNA Damage Response and Repair Pathways. J Med Chem (2017) 0.75