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1.
ChemMedChem ; 12(16): 1390-1398, 2017 08 22.
Article in English | MEDLINE | ID: mdl-28639308

ABSTRACT

Oncogenic activation of RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma, and non-small-cell lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors, and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wild-type RET (wt RET) and its mutants (e.g., V804M RET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar wt RET/V804M RET inhibitor, N-(2-fluoro-5-trifluoromethylphenyl)-N'-{4'-[(2''-benzamido)pyridin-4''-ylamino]phenyl}urea (69), endowed with a 4-anilinopyridine structure, starting from our previously identified 4-anilinopyrimidine hit compound. Profiling against a panel of kinases indicated 69 as a multi cKIT/wt RET/V804M RET inhibitor.


Subject(s)
Aminopyridines/chemistry , Phenylurea Compounds/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-ret/metabolism , Aminopyridines/chemical synthesis , Aminopyridines/toxicity , Binding Sites , Cell Line, Tumor , Drug Evaluation, Preclinical , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , Molecular Docking Simulation , Mutation , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/toxicity , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Proto-Oncogene Proteins c-ret/antagonists & inhibitors , Proto-Oncogene Proteins c-ret/genetics , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/pharmacology
2.
Bioorg Med Chem Lett ; 26(20): 4875-4878, 2016 10 15.
Article in English | MEDLINE | ID: mdl-27665377

ABSTRACT

An unpredicted condensation of naphthylamine with two molecules of ethyl propiolate yields directly carbethoxy benzoquinoline in high yield. Some benzoquinoline carboxamide derivatives with protonatable side chains were then synthesized and evaluated for antiproliferative activity on human tumor cell lines. The most active compound (7a) demonstrated to intercalate into DNA and to inhibit the relaxation activity mediated by topoisomerase II.


Subject(s)
Alkynes/chemistry , Amines/chemistry , Propionates/chemistry , Quinolines/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Quinolines/chemistry
3.
Eur J Med Chem ; 115: 416-25, 2016 Jun 10.
Article in English | MEDLINE | ID: mdl-27035798

ABSTRACT

Some new 3-substituted quinazolinones were synthesized and evaluated as inhibitors of kinases involved in fibrogenic process. The compounds were tested against a panel of both tyrosine and serine-threonine kinases. The profile of selectivity of some representative compounds was investigated through molecular docking studies. The most interesting compounds were also evaluated in vitro as potential agents for the treatment of fibrotic diseases. Quinazolinone derivatives reduced proliferation and expression of genes involved in the fibrogenic process in hepatic stellate cells (HSCs) and intestinal subepithelial myofibroblasts (ISEMFs). Furthermore some compounds downregulated phosphorylation of p38MAPK. Our findings provide evidences that 3-substituted quinazolinones target multiple essential pathways of the fibrogenic process.


Subject(s)
Enzyme Inhibitors/therapeutic use , Fibrosis/drug therapy , Quinazolinones/therapeutic use , Molecular Docking Simulation
4.
Sci Rep ; 5: 16750, 2015 Nov 16.
Article in English | MEDLINE | ID: mdl-26568452

ABSTRACT

Kinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent literature has highlighted the importance of multi target kinase inhibitors, although a correct balance between specificity and non-specificity is required. In this view, the discovery of multi-tyrosine kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the synthesis and the preliminary kinase profiling of a set of novel 4-anilinopyrimidines. Among the synthesized compounds, the N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives selectively targeted some members of class III receptor tyrosine kinase family. Starting from the structure of hit compound 19 we synthesized a further compound with an improved affinity toward the class III receptor tyrosine kinase members and endowed with a promising antitumor activity both in vitro and in vivo in a murine solid tumor model. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds.


Subject(s)
Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Urea/analogs & derivatives , Animals , Binding Sites , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptor Protein-Tyrosine Kinases , Structure-Activity Relationship , Transplantation, Heterologous , Urea/chemical synthesis , Urea/pharmacology
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