RESUMO
The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the structurally similar but functional opposing homolog FKBP52, and all known FKBP ligands are unselective. Here, we report the discovery of the potent and highly selective inhibitors of FKBP51, SAFit1 and SAFit2. This new class of ligands achieves selectivity for FKBP51 by an induced-fit mechanism that is much less favorable for FKBP52. By using these ligands, we demonstrate that selective inhibition of FKBP51 enhances neurite elongation in neuronal cultures and improves neuroendocrine feedback and stress-coping behavior in mice. Our findings provide the structural and functional basis for the development of mechanistically new antidepressants.
Assuntos
Proteínas de Ligação a Tacrolimo/antagonistas & inibidores , Adaptação Psicológica/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Células Cultivadas , Descoberta de Drogas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Neuritos/efeitos dos fármacos , Conformação Proteica , Proteínas de Ligação a Tacrolimo/química , Proteínas de Ligação a Tacrolimo/efeitos dos fármacosRESUMO
Anxiety-related psychiatric disorders represent one of the largest health burdens worldwide. Single nucleotide polymorphisms of the FK506 binding protein 51 (FKBP51) gene have been repeatedly associated with anxiety-related disorders and stress sensitivity. Given the intimate relationship of stress and anxiety, we hypothesized that amygdala FKBP51 may mediate anxiety-related behaviors. Mimicking the stress effect by specifically overexpressing FKBP51 in the basolateral amygdala (BLA) or central amygdala resulted in increased anxiety-related behavior, respectively. In contrast, application of a highly selective FKBP51 point mutant antagonist, following FKBP51(mut) BLA-overexpression, reduced the anxiogenic phenotype. We subsequently tested a novel FKBP51 antagonist, SAFit2, in wild-type mice via BLA microinjections, which reduced anxiety-related behavior. Remarkably, the same effect was observed following peripheral administration of SAFit2. To our knowledge, this is the first in vivo study using a specific FKBP51 antagonist, thereby unraveling the role of FKBP51 and its potential as a novel drug target for the improved treatment of anxiety-related disorders.
Assuntos
Ansiolíticos/administração & dosagem , Ansiedade/metabolismo , Proteínas de Ligação a Tacrolimo/antagonistas & inibidores , Proteínas de Ligação a Tacrolimo/biossíntese , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microinjeções/métodos , Fatores de RiscoRESUMO
Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAYâ 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAYâ 1143572 exhibited the best overall profile inâ vitro and inâ vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAYâ 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.
Assuntos
Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/uso terapêutico , Triazinas/uso terapêutico , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Quinase 9 Dependente de Ciclina/metabolismo , Meia-Vida , Células HeLa , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Camundongos , Camundongos Nus , Conformação Molecular , Simulação de Acoplamento Molecular , Neoplasias/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Estrutura Terciária de Proteína , Ratos , Ratos Nus , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/toxicidade , Transplante Heterólogo , Triazinas/química , Triazinas/toxicidadeRESUMO
The synthesis and biological activity of analogues containing spiro piperidinylpyridine and pyrrolidinylpyridine templates are described. The potent activity of these compounds as platelet aggregation inhibitors demonstrates the utility of the spiro structures as central template for nonpeptide RGD mimics.