RESUMO
The pharmacological inhibition of general transcriptional regulators has the potential to block growth through targeting multiple tumorigenic signalling pathways simultaneously. Here, using an innovative cell-based screen, we identify a structurally unique small molecule (named JIB-04) that specifically inhibits the activity of the Jumonji family of histone demethylases in vitro, in cancer cells, and in tumours in vivo. Unlike known inhibitors, JIB-04 is not a competitive inhibitor of α-ketoglutarate. In cancer, but not in patient-matched normal cells, JIB-04 alters a subset of transcriptional pathways and blocks viability. In mice, JIB-04 reduces tumour burden and prolongs survival. Importantly, we find that patients with breast tumours that overexpress Jumonji demethylases have significantly lower survival. Thus, JIB-04, a novel inhibitor of Jumonji demethylases in vitro and in vivo, constitutes a unique potential therapeutic and research tool against cancer, and validates the use of unbiased cellular screens to discover chemical modulators with disease relevance.
Assuntos
Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Hidrazonas/farmacologia , Hidrazonas/uso terapêutico , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Aminopiridinas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Histonas/metabolismo , Humanos , Hidrazonas/química , Concentração Inibidora 50 , Isomerismo , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Lisina/metabolismo , Metilação/efeitos dos fármacos , Camundongos , Neoplasias/genética , Bibliotecas de Moléculas Pequenas/química , Análise de Sobrevida , Transcrição Gênica/efeitos dos fármacosRESUMO
A new benzoquinone-type retro-dihydrochalcone, named evelynin, was isolated from the roots and rhizomes of Tacca chantrieri. The structure was elucidated on the basis of the analysis of spectroscopic data and confirmed by a simple one-step total synthesis. Evelynin exhibited cytotoxicity against four human cancer cell lines, MDA-MB-435 melanoma, MDA-MB-231 breast, PC-3 prostate, and HeLa cervical carcinoma cells, with IC(50) values of 4.1, 3.9, 4.7, and 6.3 µM, respectively.