ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Benzofurans/pharmacology , Biological Products/pharmacology , Eukaryotic Initiation Factor-4A/antagonists & inhibitors , Triterpenes/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzofurans/chemical synthesis , Benzofurans/chemistry , Biological Products/chemical synthesis , Biological Products/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Eukaryotic Initiation Factor-4A/metabolism , Humans , Molecular Structure , Structure-Activity Relationship , Triterpenes/chemical synthesis , Triterpenes/chemistryABSTRACT
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.
Subject(s)
Eukaryotic Initiation Factor-4A/antagonists & inhibitors , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/pathology , Oncogenes , Protein Biosynthesis/genetics , RNA, Messenger/genetics , Animals , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Eukaryotic Initiation Factor-4A/metabolism , Female , Humans , Mice, Inbred NOD , Mice, SCID , PTEN Phosphohydrolase/metabolism , RNA, Messenger/metabolism , TOR Serine-Threonine Kinases/metabolism , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Benzofurans/chemistry , Eukaryotic Initiation Factor-4A/antagonists & inhibitors , Binding Sites , Biological Products , Eukaryotic Initiation Factor-4A/metabolism , Humans , Molecular StructureABSTRACT
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.
Subject(s)
Chemistry, Pharmaceutical/methods , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/metabolism , Pyrimidines/pharmacology , Crystallography, X-Ray/methods , Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Drug Design , Humans , Inhibitory Concentration 50 , MAP Kinase Signaling System , Models, Chemical , Protein Isoforms , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , Urea/chemistryABSTRACT
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.
