RESUMO
Flavaglines such as silvestrol (1) and rocaglamide (2) constitute an interesting class of natural products with promising anticancer activities. Their mode of action is based on inhibition of eukaryotic initiation factor 4A (eIF4A) dependent translation through formation of a stable ternary complex with eIF4A and mRNA, thus blocking ribosome scanning. Herein we describe initial SAR studies in a novel series of 1-aminomethyl substituted flavagline-inspired eIF4A inhibitors. We discovered that a variety of N-substitutions at the 1-aminomethyl group are tolerated, making this position pertinent for property and ADME profile tuning. The findings presented herein are relevant to future drug design efforts towards novel eIF4A inhibitors with drug-like properties.
Assuntos
Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Produtos Biológicos/farmacologia , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Triterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzofuranos/síntese química , Benzofuranos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fator de Iniciação 4A em Eucariotos/metabolismo , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/químicaRESUMO
The serine/threonine specific protein kinase B-Raf is part of the MAPK pathway and is an interesting oncology target. We have identified thieno[2,3-d]pyrimidines as a core scaffold of small molecule B-Raf inhibitors. The SAR of analogs in this series will be described.
Assuntos
Química Farmacêutica/métodos , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirimidinas/farmacologia , Cristalografia por Raios X/métodos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Sistema de Sinalização das MAP Quinases , Modelos Químicos , Isoformas de Proteínas , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Ureia/químicaRESUMO
The PI3K/AKT/mTOR pathway is often activated in lymphoma through alterations in PI3K, PTEN, and B-cell receptor signaling, leading to dysregulation of eIF4A (through its regulators, eIF4B, eIF4G, and PDCD4) and the eIF4F complex. Activation of eIF4F has a direct role in tumorigenesis due to increased synthesis of oncogenes that are dependent on enhanced eIF4A RNA helicase activity for translation. eFT226, which inhibits translation of specific mRNAs by promoting eIF4A1 binding to 5'-untranslated regions (UTR) containing polypurine and/or G-quadruplex recognition motifs, shows potent antiproliferative activity and significant in vivo efficacy against a panel of diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma models with ≤1 mg/kg/week intravenous administration. Evaluation of predictive markers of sensitivity or resistance has shown that activation of eIF4A, mediated by mTOR signaling, correlated with eFT226 sensitivity in in vivo xenograft models. Mutation of PTEN is associated with reduced apoptosis in vitro and diminished efficacy in vivo in response to eFT226. In models evaluated with PTEN loss, AKT was stimulated without a corresponding increase in mTOR activation. AKT activation leads to the degradation of PDCD4, which can alter eIF4F complex formation. The association of eFT226 activity with PTEN/PI3K/mTOR pathway regulation of mRNA translation provides a means to identify patient subsets during clinical development.
Assuntos
Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Linfoma de Células B/genética , Linfoma de Células B/patologia , Oncogenes , Biossíntese de Proteínas/genética , RNA Mensageiro/genética , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator de Iniciação 4A em Eucariotos/metabolismo , Feminino , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , PTEN Fosfo-Hidrolase/metabolismo , RNA Mensageiro/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Rocaglates, rocaglamides, and related flavagline natural products exert their remarkable anticancer activity through inhibition of eukaryotic initiation factor 4A (eIF4A) but generally display suboptimal drug-like properties. In our efforts to identify potent drug-like eIF4A inhibitors, we developed synthetic strategies for diastereoselectively functionalizing the C1 position of aza-rocaglamide scaffolds (cf. 14 and 18), which proceed via retention or inversion of configuration at C1 depending on the C2 substituent (cf. 15 and 21) and ultimately enabled the discovery of novel and potent eIF4A inhibitors such as 25.
Assuntos
Benzofuranos/química , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Sítios de Ligação , Produtos Biológicos , Fator de Iniciação 4A em Eucariotos/metabolismo , Humanos , Estrutura MolecularRESUMO
Polyene macrolide antibiotics are naturally occurring antifungal agents. Members of this class include amphotericin B, which has been used widely to treat systemic fungal infections. A general synthetic strategy has been devised to prepare polyol chains associated with the polyene macrolides. Cyanohydrin acetonide alkylations were used to assemble the carbon skeleton, and a simple modification of the strategy allowed an advanced intermediate to be converted to either the candidin polyol or the nystatin polyol. The candidin polyol was further elaborated to a protected candidin aglycone. This strategy will be applicable to other members of the polyene macrolide natural products.