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1.
Nature ; 455(7215): 975-8, 2008 Oct 16.
Article in English | MEDLINE | ID: mdl-18923525

ABSTRACT

Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.


Subject(s)
Mutation/genetics , Neuroblastoma/genetics , Neuroblastoma/therapy , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/genetics , Alleles , Anaplastic Lymphoma Kinase , Animals , Apoptosis , Cell Line, Tumor , Cell Proliferation , Cell Survival , Enzyme Activation/genetics , Genome, Human/genetics , Humans , In Situ Hybridization, Fluorescence , In Situ Nick-End Labeling , Mice , Neuroblastoma/enzymology , Neuroblastoma/pathology , Polymorphism, Single Nucleotide/genetics , Protein Structure, Tertiary/genetics , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/metabolism , Receptor Protein-Tyrosine Kinases , Sequence Analysis, DNA
3.
Antimicrob Agents Chemother ; 49(12): 4942-9, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16304156

ABSTRACT

We report the structure-guided discovery, synthesis, and initial characterization of 3,5-diamino-piperidinyl triazines (DAPT), a novel translation inhibitor class that targets bacterial rRNA and exhibits broad-spectrum antibacterial activity. DAPT compounds were designed as structural mimetics of aminoglycoside antibiotics which bind to the bacterial ribosomal decoding site and thereby interfere with translational fidelity. We found that DAPT compounds bind to oligonucleotide models of decoding-site RNA, inhibit translation in vitro, and induce translation misincorporation in vivo, in agreement with a mechanism of action at the ribosomal decoding site. The novel DAPT antibacterials inhibit growth of gram-positive and gram-negative bacteria, including the respiratory pathogen Pseudomonas aeruginosa, and display low toxicity to human cell lines. In a mouse protection model, an advanced DAPT compound demonstrated efficacy against an Escherichia coli infection at a 50% protective dose of 2.4 mg/kg of body weight by single-dose intravenous administration.


Subject(s)
Aminoglycosides/pharmacology , Protein Biosynthesis/drug effects , Anti-Bacterial Agents/pharmacology , Biomimetic Materials/chemistry , Biomimetic Materials/pharmacology , Drug Design , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Piperidines/pharmacology , Protein Conformation , Ribosomes/drug effects , Structure-Activity Relationship , Triazines/pharmacology
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