RESUMO
Sixteen linear and cyclic peptides were designed de novo to target the C-terminus of heat shock protein 90 (Hsp90). Protein binding data indicates that three compounds directly block co-chaperone access to Hsp90's C-terminus and luciferase renaturation assays confirm Hsp90-mediated protein folding is disrupted. This is the first report of an inhibitor that binds directly to the C-terminal MEEVD region of Hsp90.
Assuntos
Sistemas de Liberação de Medicamentos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Sequência de Aminoácidos , Sítios de Ligação , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Dados de Sequência Molecular , Ligação Proteica , Estrutura Terciária de ProteínaRESUMO
The cellular protection mechanism, the heat shock response, is only activated by classical heat shock 90 inhibitors (Hsp90) that "target" the N-terminus of the protein, but not by those that modulate the C-terminus. Significant differences in cytotoxicity (nanomolar) for classical inhibitors versus their ability to modulate Hsp90 (low micromolar) are discussed. In contrast, molecules that modulate Hsp90's C-terminus show similar IC50 values for cytotoxicity and Hsp90 inhibition. A comparison between the two types of Hsp90 inhibitors suggests that classical inhibitors may be modulating an alternative biological target that stresses the cell rather directly inhibiting Hsp90, whereas C-terminal modulators are most likely acting by directly inhibiting Hsp90.
Assuntos
Proteínas de Choque Térmico HSP90/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Desenho de Fármacos , Células HCT116 , Humanos , Concentração Inibidora 50 , Neoplasias/metabolismo , Fenótipo , Ligação Proteica , Dobramento de Proteína , Estrutura Terciária de Proteína , RNA Mensageiro/química , TemperaturaRESUMO
Blocking the function of both heat shock protein 90 and 70 (Hsp90 and Hsp70) simultaneously limits these chaperones' cytoprotective effects on cancer cells. The unique phenotype associated with modulating Hsp90's C-terminus, when used in combination with Hsp70 inhibitors, produces a synergistic and highly relevant dual chemotherapy regimen.
Assuntos
Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Luciferases/metabolismo , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Classic oncogenic heat shock protein 90 (Hsp90) inhibitors target the N-terminus of the protein, triggering a survival mechanism in cancer cells referred to as the heat shock response (HSR). Inhibiting Hsp90 by modulating the C-terminus does not trigger a HSR, making it a highly attractive chemotherapeutic approach.
Assuntos
Benzoquinonas/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/química , Lactamas Macrocíclicas/farmacologia , Peptídeos Cíclicos/farmacologia , Células HCT116 , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Resposta ao Choque Térmico/efeitos dos fármacos , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Fenótipo , Conformação Proteica , Dobramento de Proteína , RNA Mensageiro/metabolismoRESUMO
Both heat shock protein 90 and 70 (Hsp90, Hsp70) are cytoprotective proteins that regulate cell death by stabilizing and folding proteins. Taking a two-pronged approach, involving simultaneous inhibition of Hsp90 and Hsp70, leads to synergistic cell death, which makes this is an appealing clinical therapy.
Assuntos
Antineoplásicos/farmacologia , Citoproteção/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias/metabolismo , Peptídeos Cíclicos/farmacologia , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Células HeLa , Humanos , Conformação Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Peptídeos Cíclicos/química , Relação Estrutura-AtividadeRESUMO
A series of C32-O-aralkyl ether derivatives of the FK-506 related macrolide ascomycin have been prepared based on an earlier reported C32-O-cinnamyl ether design. In the present study, the nature of the aryl tethering group was varied in an attempt to improve oral activity. An imidazol-2-yl-methyl tether was found to be superior among those investigated and has resulted in an ascomycin analog, L-733,725, with in vivo immunosuppressive activity comparable to FK-506 but with an improved therapeutic index.
