RESUMO
Cdk9 is a key elongation factor for RNA transcription and functions by phosphorylating the C-terminal domain of RNA polymerase II. Here we present direct evidence that cdk9 is important for cancer cell survival and describe the characterization of the potent cdk9 inhibitor CDKI-73 in primary human leukemia cells. CDKI-73 induced caspase-dependent apoptosis that was preceded by dephosphorylation of cdk9 and serine 2 of RNA polymerase II. CDKI-73 was more potent than the pan-cdk inhibitor flavopiridol and showed >200-fold selectivity against primary leukemia cells when compared with normal CD34+ cells. Furthermore, CDKI-73 was equipotent in poor prognostic sub-groups of leukemia patients and showed cytotoxic synergy with the nucleoside analog fludarabine. The Mechanism of synergy was associated with CDKI-73-mediated transcriptional inhibition of MCL1 and XIAP that was maintained when used in combination with fludarabine. Our data present a strong rationale for the development of cdk9 inhibitors such as CDKI-73 as anticancer therapeutics.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Vidarabina/análogos & derivados , Animais , Apoptose , Estudos de Casos e Controles , Quinase 9 Dependente de Ciclina/genética , Sinergismo Farmacológico , Células HEK293 , Humanos , Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , Fosforilação , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Transcrição Gênica/efeitos dos fármacos , Vidarabina/administração & dosagem , Vidarabina/farmacologiaRESUMO
A series of 2,4,5-trisubstituted pyrimidines have been synthesised and characterised, which exhibited potent CDK inhibition and anti-proliferative activities. The structure-activity relationship is analysed and a rational for CDK9 selectivity is discussed. Compound 9s, possessing appreciable selectivity for CDK9 over other CDKs, is capable of activating caspase 3, reducing the level of Mcl-1 anti-apoptotic protein, and inducing cancer cell apoptosis.
Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Quinases Ciclina-Dependentes/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
A series of N-phenyl-imidazo[4,5-b]pyridin-2-amines, 4-indazolyl-N-phenylpyrimidin-2-amines and N-phenyl-4-pyrazolo[3,4-b]pyridin-pyrimidin-2-amines have been synthesized. Their anti-proliferative activities were tested in HCT-116 human colon carcinoma and MCF-7 breast carcinoma cell lines. Many exhibited potent anti-proliferative and CDK9 inhibitory activities. A lead compound 18b demonstrated the ability to reduce the level of Mcl-1 anti-apoptotic protein, to activate caspase 3/7 and induce cancer cell apoptosis.
