RESUMO
The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound 13 was identified, which potently (IC50 < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines. Pharmacokinetic optimization of 13 by prodrug strategies resulted in orally bioavailable 25, which demonstrated an 8-fold higher oral AUC (F = 62.3%). Pharmacodynamic studies of 25 showed it to effectively reduce cMYC protein levels, leading to >80% tumor regression of NCI-H446 SCLC xenograft tumors in mice. These results support the potential of 25 for the treatment of MYC-amplified cancers including SCLC.
Assuntos
Aurora Quinase A/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pirimidinas/química , Animais , Aurora Quinase A/metabolismo , Aurora Quinase B/antagonistas & inibidores , Aurora Quinase B/metabolismo , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Mobilização de Células-Tronco Hematopoéticas , Receptores CXCR4/antagonistas & inibidores , Animais , Benzilaminas , Ciclamos , Avaliação Pré-Clínica de Medicamentos , Células-Tronco Hematopoéticas/citologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Poliaminas/química , Pirimidinas/química , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacologia , Receptores CXCR4/metabolismo , Medicina RegenerativaAssuntos
Fármacos Antiobesidade/química , Pirazóis/química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Tiofenos/química , Animais , Fármacos Antiobesidade/farmacologia , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Agonismo Inverso de Drogas , Humanos , Hipotermia/tratamento farmacológico , Masculino , Pirazóis/síntese química , Pirazóis/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/farmacocinéticaRESUMO
The purpose of this study was to determine the effect of zinc supplementation on radiation-induced mucositis in patients with nasopharyngeal carcinoma (NPC) and those with oral cancers (OC). A total of 100 patients with head and neck cancers engaged in a randomized double blind study. All participants were placed into two randomized groups (experimental and control). The experimental group received a standard dose of zinc supplements, and the control group was given a placebo. Subgroup analyses were performed between 40 NPC and 43 OC patients. It was found that patients with OC in the control group developed Grade 2 and Grade 3 mucositis sooner than those in the experimental group. However, the benefits were not found to extend to patients with NPC. The results indicated that zinc supplementation prescribed in conjunction with radiotherapy postponed the development of severe mucositis solely for patients with OC. The pretreatment oral mucosa condition and areca chewing habit might account for such discrepancy.