RESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Janus Quinases/antagonistas & inibidores , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Quinases da Família src/antagonistas & inibidores , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Desenho de Fármacos , Humanos , Janus Quinases/química , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/química , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/químicaRESUMO
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.
Assuntos
Compostos Benzidrílicos/síntese química , Compostos Benzidrílicos/farmacologia , Cresóis/síntese química , Cresóis/farmacologia , Desenho de Fármacos , Ácidos Mandélicos/síntese química , Ácidos Mandélicos/farmacologia , Fenilpropanolamina/síntese química , Fenilpropanolamina/farmacologia , Animais , Compostos Benzidrílicos/metabolismo , Sítios de Ligação/efeitos dos fármacos , Cresóis/metabolismo , Ácidos Mandélicos/metabolismo , Fenilpropanolamina/metabolismo , Ratos , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M3/metabolismo , Relação Estrutura-Atividade , Tartarato de TolterodinaRESUMO
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.
