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Future Med Chem ; 11(20): 2715-2734, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31571504


Proteolysis-targeting chimeras (PROTACs) have received much attention for their promising therapeutic intervention in recent years. These molecules, with the mechanism of simultaneous recruitment of target protein and an E3 ligase, can trigger the cellular ubiquitin-proteasome system to degrade the target proteins. This article systematically introduces the mechanism of small-molecule PROTACs, and summarized the research progress of small-molecule PROTACs. The prospect for further application and the problems to be solved are also discussed.

Eur J Med Chem ; 179: 502-514, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276895


Inhibition of BET family of bromodomain is an appealing intervention strategy for several cancers and inflammatory diseases. This article highlights our work toward the identification of potent, selective, and efficacious BET inhibitors using a structure-based approach focused on improving potency. Our medicinal chemistry efforts led to the identification of compound 24, a novel phenanthridin-6(5H)-one derivative, as a potent (IC50 = 0.24 µM) and selective BET inhibitor with excellent cancer cell lines inhibitory activities and favorable oral pharmacokinetic properties.

Antineoplásicos/farmacologia , Desenho de Drogas , Proteínas Nucleares/antagonistas & inibidores , Fenantridinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Feminino , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Proteínas Nucleares/metabolismo , Fenantridinas/administração & dosagem , Fenantridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
J Enzyme Inhib Med Chem ; 34(1): 808-817, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30879350


The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer, inflammation, obesity, and cardiovascular disease. Recently, the discovery of novel BRD4 inhibitors has garnered substantial interest. Starting from scaffold hopping of the reported compound dihydroquinazolinone (PFI-1), a series of coumarin derivatives were designed and synthesised as a new chemotype of BRD4 inhibitors. Interestingly, the representative compounds 13 exhibited potent BRD4 binding affinity and cell proliferation inhibitory activity, and especially displayed a favourable PK profile with high oral bioavailability (F = 49.38%) and metabolic stability (T1/2 = 4.2 h), meaningfully making it as a promising lead compound for further drug development.

Cumarínicos/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Administração Oral , Proteínas de Ciclo Celular , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cumarínicos/administração & dosagem , Cumarínicos/farmacocinética , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Concentração Inibidora 50 , Quinazolinonas/química , Relação Estrutura-Atividade