ABSTRACT
Tumor survival, metastases, chemoresistance, and escape from immune responses have been associated with inappropriate activation of STAT3 and/or STAT5 in various cancers, including solid tumors. Debio 0617B has been developed as a first-in-class kinase inhibitor with a unique profile targeting phospho-STAT3 (pSTAT3) and/or pSTAT5 in tumors through combined inhibition of JAK, SRC, ABL, and class III/V receptor tyrosine kinases (RTK). Debio 0617B showed dose-dependent inhibition of pSTAT3 in STAT3-activated carcinoma cell lines; Debio 0617B also showed potent antiproliferative activity in a panel of cancer cell lines and in patient-derived tumor xenografts tested in an in vitro clonogenic assay. Debio 0617B showed in vivo efficacy by inhibiting tumor growth in several mouse xenograft models. To increase in vivo efficacy and STAT3 inhibition, Debio 0617B was tested in combination with the EGFR inhibitor erlotinib in a non-small cell lung cancer xenograft model. To evaluate the impact of in vivo STAT3 blockade on metastases, Debio 0617B was tested in an orthotopic tumor model. Measurement of primary tumor weight and metastatic counts in lung tissue demonstrated therapeutic efficacy of Debio 0617B in this model. These data show potent activity of Debio 0617B on a broad spectrum of STAT3-driven solid tumors and synergistic activity in combination with EGFR inhibition. Mol Cancer Ther; 15(10); 2334-43. ©2016 AACR.
Subject(s)
Antineoplastic Agents/pharmacology , Janus Kinases/antagonists & inhibitors , Neoplasms/metabolism , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , STAT3 Transcription Factor/metabolism , src-Family Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Disease Models, Animal , Drug Design , Humans , Janus Kinases/chemistry , Mice , Molecular Conformation , Molecular Docking Simulation , Molecular Dynamics Simulation , Neoplasm Metastasis , Neoplasms/drug therapy , Neoplasms/pathology , Protein Kinase Inhibitors/chemistry , Receptor Protein-Tyrosine Kinases/chemistry , Signal Transduction/drug effects , Tumor Burden/drug effects , Xenograft Model Antitumor Assays , src-Family Kinases/chemistryABSTRACT
A number of oxalamide derivatives have been synthesized and evaluated for PAI-1 inhibitory activity. In vitro PAI-1 inhibitory activities of oxalamide derivatives are evaluated by chromogenic assay. Few compounds have shown significant PAI-1 inhibitory activity.
Subject(s)
Amides/chemistry , Oxamic Acid/pharmacology , Plasminogen Activator Inhibitor 1/chemistry , Plasminogen Activator Inhibitor 1/metabolism , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/metabolism , Humans , Inhibitory Concentration 50 , Oxamic Acid/chemistry , Tissue Plasminogen Activator/metabolismABSTRACT
Novel derivatives of Tolterodine (1) and Oxybutynin (2) have been designed using conformationally restricted azabicyclics as replacement for open-chain amines. The synthesis and structure-activity relationships are presented.
Subject(s)
Benzhydryl Compounds/chemical synthesis , Benzhydryl Compounds/pharmacology , Cresols/chemical synthesis , Cresols/pharmacology , Drug Design , Mandelic Acids/chemical synthesis , Mandelic Acids/pharmacology , Phenylpropanolamine/chemical synthesis , Phenylpropanolamine/pharmacology , Animals , Benzhydryl Compounds/metabolism , Binding Sites/drug effects , Cresols/metabolism , Mandelic Acids/metabolism , Phenylpropanolamine/metabolism , Rats , Receptor, Muscarinic M2/metabolism , Receptor, Muscarinic M3/metabolism , Structure-Activity Relationship , Tolterodine TartrateABSTRACT
Two meso-tetra[(nido-carboranylmethyl)phenyl]porphyrins (para- and meta-regioisomers) and their corresponding Zn(II) complexes have been synthesized with the aim of studying the effect of carborane distribution and metalation on the biological properties of this series of compounds. In vitro cell toxicity, uptake/efflux, and subcellular localization using rat 9L, mouse B16 and/or human U-373MG cells were evaluated. All four amphiphilic porphyrins display very low cytotoxicities and time- and concentration-dependent uptake by cells, which is influenced by serum proteins. Preliminary subcellular localization studies suggest that one of these compounds localizes in close proximity to the cell nucleus. All four nido-carboranylporphyrins show promise as boron-carriers for the boron neutron capture therapy of cancers, particularly the metal-free nido-carboranylporphyrins 5 and 12, which are able to deliver higher amount of boron to cells in vitro than the corresponding zinc complexes.
