RESUMEN
The therapeutic and toxic effects of drugs are often generated through effects on distinct cell types in the body. Selective delivery of drugs to specific cells or cell lineages would, therefore, have major advantages, in particular, the potential to significantly improve the therapeutic window of an agent. Cells of the monocyte-macrophage lineage represent an important target for many therapeutic agents because of their central involvement in a wide range of diseases including inflammation, cancer, atherosclerosis, and diabetes. We have developed a versatile chemistry platform that is designed to enhance the potency and delivery of small-molecule drugs to intracellular molecular targets. One facet of the technology involves the selective delivery of drugs to cells of the monocyte-macrophage lineage, using the intracellular carboxylesterase, human carboxylesterase-1 (hCE-1), which is expressed predominantly in these cells. Here, we demonstrate selective delivery of many types of intracellularly targeted small molecules to monocytes and macrophages by attaching a small esterase-sensitive chemical motif (ESM) that is selectively hydrolyzed within these cells to a charged, pharmacologically active drug. ESM versions of histone deacetylase (HDAC) inhibitors, for example, are extremely potent anticytokine and antiarthritic agents with a wider therapeutic window than conventional HDAC inhibitors. In human blood, effects on monocytes (hCE-1-positive) are seen at concentrations 1000-fold lower than those that affect other cell types (hCE-1-negative). Chemical conjugates of this type, by limiting effects on other cells, could find widespread applicability in the treatment of human diseases where monocyte-macrophages play a key role in disease pathology.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Esterasas/antagonistas & inhibidores , Esterasas/química , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Aminoácidos/química , Animales , Anisomicina/farmacología , Artritis/inmunología , Carboxilesterasa/antagonistas & inhibidores , Carboxilesterasa/química , Carboxilesterasa/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citocinas/biosíntesis , Citocinas/sangre , Citocinas/genética , Inhibidores Enzimáticos/farmacología , Esterasas/genética , Ésteres/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lipopolisacáridos/farmacología , Espectroscopía de Resonancia Magnética , Ratones , Ratones Transgénicos , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/sangre , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Inhibition of histone deacetylase activity represents a promising new modality in the treatment of a number of cancers. A novel HDAC series demonstrating inhibitory activity in cell proliferation assays is described. Optimisation based on the introduction of basic amine linkers to effect good drug distribution to tumour led to the identification of a compound with oral activity in a human colon cancer xenograft study associated with increased histone H3 acetylation in tumour tissue.
