Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.

Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-cyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure-metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC(50) = 2.3 nM, K(B) = 760 pM) and of the isolated rat receptor (IC(50) = 430 pM, K(B) = 380 pM). Glucagon-stimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (K(i) = 14 nM). This compound was orally available in dogs (F(po) = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.

Aminoglycoside antibiotics target an internal RNA loop within the bacterial ribosomal decoding site. Here, we described the synthesis and SAR of novel 3,5-diamino-piperidine derivatives as aminoglycoside mimetics, and show they act as inhibitors of bacterial translation and growth. KeywordsAminoglycosides; Antibiotics; Translation inhibitors; 2-deoxy-streptamine; Ribosome; Decoding site; 3; 5-diamino-piperidine Bacterial resistance to antibiotics is on the rise and represents a global medical threat. In hospitals in the United States, approximately two million patients per year are infected. 1 The majority of these nosocomial pathogens are resistant to at least one antibiotic and result in about 90,000 deaths per year; a number that has increased 7-fold over the last decade. The recent and rapid spread of community acquired methicillin resistant Staphylococcus aureus further highlights the threat of resistance development and illustrates the need for new antibiotics that work by novel mechanisms. 2 Given the broad genetic and physiological diversity of bacterial pathogens and the need for empiric therapies that cover a broad panel of organisms, it is not surprising that discovery of new antibiotics has advanced slowly. Central to antibiotic discovery is identifying broadly validated targets. One such proven target is the bacterial ribosome, which is the target for a significant number of clinically important antibiotics that bind at the ribosomal RNA (rRNA). 3 Here, we expand on the description of a novel series of antibacterial compounds that target rRNA and blocks bacterial translation and growth. 4Three-dimensional structures of different aminoglycosides bound to the decoding site, or Asite, within the 16S rRNA have been determined by X-ray crystallography. 5 Importantly, these studies have shown that 2-deoxystreptamine (2-DOS), a conserved core scaffold among aminoglycosides, binds in a similar manner regardless of the 4,5-or 4,6-disubstitutions found in the neomycin or gentamicin families, respectively (Fig. 1) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript groups of 2-DOS are predominantly involved in base recognition by forming conserved hydrogen bonds with A1493, G1494 and U1495 of the 16S rRNA. These interactions anchor the aminoglycoside scaffold within the A-site internal loop and displace residues A1492 and A1493 from the RNA interior. These two adenine residues act as a molecular switch that is involved in securing the fidelity of translation by interacting w...

We report the structure-guided discovery, synthesis, and initial characterization of 3,5-diamino-piperidinyl triazines (DAPT), a novel translation inhibitor class that targets bacterial rRNA and exhibits broad-spectrum antibacterial activity. DAPT compounds were designed as structural mimetics of aminoglycoside antibiotics which bind to the bacterial ribosomal decoding site and thereby interfere with translational fidelity. We found that DAPT compounds bind to oligonucleotide models of decoding-site RNA, inhibit translation in vitro, and induce translation misincorporation in vivo, in agreement with a mechanism of action at the ribosomal decoding site. The novel DAPT antibacterials inhibit growth of gram-positive and gram-negative bacteria, including the respiratory pathogen Pseudomonas aeruginosa, and display low toxicity to human cell lines. In a mouse protection model, an advanced DAPT compound demonstrated efficacy against an Escherichia coli infection at a 50% protective dose of 2.4 mg/kg of body weight by single-dose intravenous administration.