Asunto(s)
Antibióticos Antineoplásicos/química , Ácidos Carboxílicos/química , Ciclopentanos/química , Streptomyces/química , Antibióticos Antineoplásicos/aislamiento & purificación , Antibióticos Antineoplásicos/farmacología , Ácidos Carboxílicos/aislamiento & purificación , Ácidos Carboxílicos/farmacología , Ciclopentanos/aislamiento & purificación , Ciclopentanos/farmacología , Células HeLa , HumanosRESUMEN
A novel series of macrocyclic compounds were designed and synthesized as multi-target inhibitors targeting HDAC, FLT3 and JAK2. Some of these compounds exhibited potent HDAC inhibition as well as FLT3 and JAK2 inhibition under both cell-free and cellular conditions. In vitro antiproliferative assay indicated that these compounds were interestingly more cytotoxic to MV4-11 cells bearing FLT3-ITD mutation and HEL cells bearing JAK2(V617F) mutation.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Histona Desacetilasas/química , Janus Quinasa 2/antagonistas & inhibidores , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Western Blotting , Proliferación Celular/efectos de los fármacos , Células HeLa , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Transducción de SeñalRESUMEN
The poly(ADP-ribose) polymerases (PARPs) is an important group of enzymes in DNA repair pathways, especially the base excision repair (BER) for DNA single-strand breaks (SSBs) repair. Inhibition of PARP in DNA repair-defective tumors (like those with BRAC1/2 mutations) can lead to cell death and genomic instability, what is so called "synthetic lethality". Currently, PARP inhibitors combined with cytotoxic chemotherapeutic agents in the treatment of BRCA-1/2 deficient cancers are in the clinical development. In this review, we will be focused on the development of combination application of PARP inhibitors with other anticancer agents in clinical trials.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Bencimidazoles/uso terapéutico , Neoplasias de la Mama/genética , Reparación del ADN , Quimioterapia Combinada , Femenino , Humanos , Indoles/uso terapéutico , Melanoma/tratamiento farmacológico , Mutación , Neoplasias Ováricas/genética , Ftalazinas/uso terapéutico , Piperazinas/uso terapéuticoRESUMEN
Signal transduction in cells plays an important role in the process of cellular metabolism, segmentation, differentiation, biological behaviors and cell death. Direct and indirect involvement of kinases in tumor growth, metastasis and apoptosis make them the most promising targets for anticancer discovery. Most of the kinase inhibitors in clinical use or in late development stages are multi-target kinase inhibitors (MTKIs). These MTKIs are demonstrated to exert potent anti-tumor effects through several different pathways. This review presents in the view of a medicinal chemistry point, a brief account and analysis of transduction pathways of representative MTKIs in clinical use or in late development stages.
Asunto(s)
Antineoplásicos/uso terapéutico , Sistemas de Liberación de Medicamentos/métodos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal , Ensayos Clínicos Fase III como Asunto , HumanosRESUMEN
Among those enzymes that regulate gene expression, histone deacetylases (HDACs) play important roles in cell cycles. Extensive studies were carried out in the field of HDACs and the applications of HDAC inhibitors (HDACIs) as chemotherapeutic interventions for diverse diseases. HDACIs have moved from laboratories to clinic uses. Huge bodies of related research results were well documented and dispersed in literature. According to our understanding, HDACIs can be broadly classified as hydroxamic acids, cyclic tetrapeptides, short chain fatty acids, benzamides and electrophilic ketones. Herein, we are going to review the design and their structure-activity relationships of HDACIs and according to their structural catalogs.