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1.
Nat Chem Biol ; 11(5): 347-354, 2015 May.
Article in English | MEDLINE | ID: mdl-25848931

ABSTRACT

Huntington's disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified new modifiers of mutant HTT toxicity by performing a large-scale 'druggable genome' siRNA screen in human cultured cells, followed by hit validation in Drosophila. We focused on glutaminyl cyclase (QPCT), which had one of the strongest effects on mutant HTT-induced toxicity and aggregation in the cell-based siRNA screen and also rescued these phenotypes in Drosophila. We found that QPCT inhibition induced the levels of the molecular chaperone αB-crystallin and reduced the aggregation of diverse proteins. We generated new QPCT inhibitors using in silico methods followed by in vitro screening, which rescued the HD-related phenotypes in cell, Drosophila and zebrafish HD models. Our data reveal a new HD druggable target affecting mutant HTT aggregation and provide proof of principle for a discovery pipeline from druggable genome screen to drug development.


Subject(s)
Aminoacyltransferases/drug effects , Aminoacyltransferases/genetics , Huntington Disease/drug therapy , Huntington Disease/genetics , RNA, Small Interfering , Aminoacyltransferases/antagonists & inhibitors , Animals , Cells, Cultured , Computational Biology , Drosophila , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Green Fluorescent Proteins/metabolism , Humans , Huntingtin Protein , Mice , Mice, Inbred C57BL , Mutation/genetics , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Neurons/metabolism , Zebrafish , alpha-Crystallin B Chain/metabolism
2.
J Med Chem ; 50(23): 5579-88, 2007 Nov 15.
Article in English | MEDLINE | ID: mdl-17929792

ABSTRACT

New pyrazolo[3,4-d]pyrimidines were synthesized and found to inhibit Src phosphorylation in a cell-free assay. Some of them significantly reduced the growth of human osteogenic sarcoma (SaOS-2) cells. The best compound, in terms of inhibitory properties toward both Src and SaOS-2 cells, was further investigated and found to reduce bone resorption when used to treat mouse osteoclasts, without interfering with normal osteoblast growth. Moreover, its metabolic stability prompted its study on a human SaOS-2 xenograft tumor model in nude mice, where the compound reduced significantly both the volume and weight of the tumor. These experimental findings make the new compound an interesting hit in the field of bone-related diseases.


Subject(s)
Bone Neoplasms/drug therapy , Cell Proliferation/drug effects , Osteosarcoma/drug therapy , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Animals , Bone Neoplasms/pathology , Bone Resorption/prevention & control , Cell Line, Tumor , Cells, Cultured , Drug Screening Assays, Antitumor , Humans , Mice , Mice, Nude , Neoplasm Transplantation , Osteoblasts/drug effects , Osteoclasts/drug effects , Osteosarcoma/pathology , Phosphorylation , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship , Transplantation, Heterologous , src-Family Kinases/antagonists & inhibitors , src-Family Kinases/metabolism
3.
Eur J Med Chem ; 95: 526-45, 2015 May 05.
Article in English | MEDLINE | ID: mdl-25847770

ABSTRACT

Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initiation, proliferation, invasion/infiltration, metastasis formation and resistance to chemotherapy. In a drug discovery project aimed at the identification of inhibitors of the canonical Wnt pathway, we selected a series of quinazoline 2,4-diones as starting point for the therapeutic treatment of glioblastoma multiforme. Despite of poor physico-chemical properties of hit compound 1, our medicinal chemistry effort allowed the discovery and characterization of lead compound 33 (SEN461), with improved ADME profile, good bioavailability and active in vitro and in vivo in glioblastoma, gastric and sarcoma tumors.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Wnt Signaling Pathway/drug effects , Animals , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Inhibitory Concentration 50 , Male , Mice , Quinazolines/metabolism , Quinazolines/pharmacokinetics , Structure-Activity Relationship , Xenograft Model Antitumor Assays
4.
Eur J Med Chem ; 58: 30-43, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23085772

ABSTRACT

Within our studies on structure-activity relationships of 4-quinolone-3-carboxamides as cannabinoid ligands, a new series of compounds characterized by a fluoro or phenylthio group at 7-position and different substituents at N1 and carboxamide nitrogen were synthesized and evaluated for their binding ability to cannabinoid type 1 (CB1) and type 2 (CB2) receptors. Most of the compounds showed affinity for one or both cannabinoid receptors at nanomolar concentration, with K(i)(CB1) and K(i)(CB2) values ranging from 2.45 to >10,000 nM and from 0.09 to 957 nM, respectively. The N-(3,4-dichlorobenzyl)amide derivatives 27 and 40 displayed relatively low affinity, but high selectivity towards the CB1 receptor. Compounds 4 and 40, a CB2 and a CB1 ligand, respectively, behaved as partial agonists in the [(35)S]GTPγS assay. They showed very low permeability through (MDCK-MDR1) cells and might, therefore, represent possible lead structures for further optimization in the search for cannabinoid ligands unable to cross the blood-brain barrier.


Subject(s)
Quinolones/pharmacology , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB2/agonists , Animals , CHO Cells , Cell Line , Cricetinae , Dogs , Dose-Response Relationship, Drug , Humans , Ligands , Molecular Structure , Quinolones/chemical synthesis , Quinolones/chemistry , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity Relationship
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